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  • 101. Huyghe, Jeroen R.
    et al.
    Bien, Stephanie A.
    Harrison, Tabitha A.
    Kang, Hyun Min
    Chen, Sai
    Schmit, Stephanie L.
    Conti, David V.
    Qu, Conghui
    Jeon, Jihyoun
    Edlund, Christopher K.
    Greenside, Peyton
    Wainberg, Michael
    Schumacher, Fredrick R.
    Smith, Joshua D.
    Levine, David M.
    Nelson, Sarah C.
    Sinnott-Armstrong, Nasa A.
    Albanes, Demetrius
    Alonso, M. Henar
    Anderson, Kristin
    Arnau-Collell, Coral
    Arndt, Volker
    Bamia, Christina
    Banbury, Barbara L.
    Baron, John A.
    Berndt, Sonja I.
    Bezieau, Stephane
    Bishop, D. Timothy
    Boehm, Juergen
    Boeing, Heiner
    Brenner, Hermann
    Brezina, Stefanie
    Buch, Stephan
    Buchanan, Daniel D.
    Burnett-Hartman, Andrea
    Butterbach, Katja
    Caan, Bette J.
    Campbell, Peter T.
    Carlson, Christopher S.
    Castellvi-Bel, Sergi
    Chan, Andrew T.
    Chang-Claude, Jenny
    Chanock, Stephen J.
    Chirlaque, Maria-Dolores
    Cho, Sang Hee
    Connolly, Charles M.
    Cross, Amanda J.
    Cuk, Katarina
    Curtis, Keith R.
    de la Chapelle, Albert
    Doheny, Kimberly F.
    Duggan, David
    Easton, Douglas F.
    Elias, Sjoerd G.
    Elliott, Faye
    English, Dallas R.
    Feskens, Edith J. M.
    Figueiredo, Jane C.
    Fischer, Rocky
    FitzGerald, Liesel M.
    Forman, David
    Gala, Manish
    Gallinger, Steven
    Gauderman, W. James
    Giles, Graham G.
    Gillanders, Elizabeth
    Gong, Jian
    Goodman, Phyllis J.
    Grady, William M.
    Grove, John S.
    Gsur, Andrea
    Gunter, Marc J.
    Haile, Robert W.
    Hampe, Jochen
    Hampel, Heather
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hayes, Richard B.
    Hofer, Philipp
    Hoffmeister, Michael
    Hopper, John L.
    Hsu, Wan-Ling
    Huang, Wen-Yi
    Hudson, Thomas J.
    Hunter, David J.
    Ibanez-Sanz, Gemma
    Idos, Gregory E.
    Ingersoll, Roxann
    Jackson, Rebecca D.
    Jacobs, Eric J.
    Jenkins, Mark A.
    Joshi, Amit D.
    Joshu, Corinne E.
    Keku, Temitope O.
    Key, Timothy J.
    Kim, Hyeong Rok
    Kobayashi, Emiko
    Kolonel, Laurence N.
    Kooperberg, Charles
    Kuehn, Tilman
    Kury, Sebastien
    Kweon, Sun-Seog
    Larsson, Susanna C.
    Laurie, Cecelia A.
    Le Marchand, Loic
    Leal, Suzanne M.
    Lee, Soo Chin
    Lejbkowicz, Flavio
    Lemire, Mathieu
    Li, Christopher I.
    Li, Li
    Lieb, Wolfgang
    Lin, Yi
    Lindblom, Annika
    Lindor, Noralane M.
    Ling, Hua
    Louie, Tin L.
    Mannisto, Satu
    Markowitz, Sanford D.
    Martin, Vicente
    Masala, Giovanna
    McNeil, Caroline E.
    Melas, Marilena
    Milne, Roger L.
    Moreno, Lorena
    Murphy, Neil
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Naccarati, Alessio
    Newcomb, Polly A.
    Offit, Kenneth
    Ogino, Shuji
    Onland-Moret, N. Charlotte
    Pardini, Barbara
    Parfrey, Patrick S.
    Pearlman, Rachel
    Perduca, Vittorio
    Pharoah, Paul D. P.
    Pinchev, Mila
    Platz, Elizabeth A.
    Prentice, Ross L.
    Pugh, Elizabeth
    Raskin, Leon
    Rennert, Gad
    Rennert, Hedy S.
    Riboli, Elio
    Rodriguez-Barranco, Miguel
    Romm, Jane
    Sakoda, Lori C.
    Schafmayer, Clemens
    Schoen, Robert E.
    Seminara, Daniela
    Shah, Mitul
    Shelford, Tameka
    Shin, Min-Ho
    Shulman, Katerina
    Sieri, Sabina
    Slattery, Martha L.
    Southey, Melissa C.
    Stadler, Zsofia K.
    Stegmaier, Christa
    Su, Yu-Ru
    Tangen, Catherine M.
    Thibodeau, Stephen N.
    Thomas, Duncan C.
    Thomas, Sushma S.
    Toland, Amanda E.
    Trichopoulou, Antonia
    Ulrich, Cornelia M.
    Van den Berg, David J.
    van Duijnhoven, Franzel J. B.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Kranen, Henk
    Vijai, Joseph
    Visvanathan, Kala
    Vodicka, Pavel
    Vodickova, Ludmila
    Vymetalkova, Veronika
    Weigl, Korbinian
    Weinstein, Stephanie J.
    White, Emily
    Win, Aung Ko
    Wolf, C. Roland
    Wolk, Alicja
    Woods, Michael O.
    Wu, Anna H.
    Zaidi, Syed H.
    Zanke, Brent W.
    Zhang, Qing
    Zheng, Wei
    Scacheri, Peter C.
    Potter, John D.
    Bassik, Michael C.
    Kundaje, Anshul
    Casey, Graham
    Moreno, Victor
    Abecasis, Goncalo R.
    Nickerson, Deborah A.
    Gruber, Stephen B.
    Hsu, Li
    Peters, Ulrike
    Discovery of common and rare genetic risk variants for colorectal cancer2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 76-+Article in journal (Refereed)
    Abstract [en]

    To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

  • 102.
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Imaging the pancreas: new aspects on lobular development and adult constitution2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mouse pancreas is a mixed exocrine and endocrine glandconsisting of three lobular compartments: the splenic, duodenal and gastric lobes. During embryogenesis, the pancreas forms from two progenitor populations located on the dorsal and ventral side of the primitive gut tube. These anlagen are brought in close proximity as the gut elongates and rotates, and fuse to form a single organ. The splenic and duodenal lobes develop from the dorsal and ventral anlagen, respectively.

    In the adult pancreas, exocrine tissue secretes digestive enzymes intothe gut lumen to support nutrient uptake. The endocrine Islets of Langerhans are scattered throughout the exocrine tissue and aid in regulation of energy homeostasis through the secretion of hormones. One of the key players in energy homeostasis is the pancreatic ß-cell, which is the most abundant cell type of the islets. The β-cells regulates blood glucose levels through the action of insulin. Conditions where this regulation does not function properly are gathered under the common name of Diabetes mellitus.

    Type 1 diabetes (T1D) is characterized by insulin deficiency due to autoimmune destruction of the ß-cells. Using recently developed protocols for optical projection tomography (OPT) whole-organ imaging, we have revealed new spatial and quantitative aspects on ß-cell mass dynamics and immune infiltration during the course of T1D development in the non-obese diabetic (NOD) mouse model. We show that although immune infiltration appears to occur asynchronously throughout the organ, smaller islets, mainly located in the periphery of the organ, preferentially loose their ß-cells during early stages of disease progression. Larger islets appear more resistant to the autoimmune attack and our data indicate the existence of a compensatory proliferative capacity within these islets. We also report the appearance of structures resembling tertiary lymphoid organs (TLOs) in association with the remaining islets during later phases of T1D progression.

    OPT has already proven to be a useful tool for assessments of ß-cellmass in the adult mouse pancreas. However, as with other techniques, previous protocols have relied on a tedious degree of manual postivacquisition editing. To further refine OPT-based assessment of pancreatic ß-cell mass distribution in the murine pancreas, we implemented a computational statistical approach, Contrast-Limited Adaptive Histogram Normalisation (CLAHE), to the OPT projection data of pancreata from C57Bl/6 mice. This methodology provided increased islet detection sensitivity, improved islet morphology and diminished subjectivity in thresholding for reconstruction and quantification. Using this approach, we could report a substantially higher number of islets than previously described for this strain and provide evidence of significant differences in islet mass distribution between the pancreatic lobes. The gastric lobe stood out in particular and contained a 75% higher islet density as compared to the splenic lobe.

    Although the development of the early pancreatic buds has been relatively well studied, later morphogenetic events are less clear and information regarding the formation of the gastric lobe has largely been missing. Using OPT we have generated a quantitative three-dimensional road map of pancreatic morphogenesis in the mouse. We show that the gastric lobe forms as a perpendicular outgrowth fromthe stem of the dorsal pancreas at around embryonic day (e) 13.5, which grows into a mesenchymal domain overlaying the pyloric sphincter and proximal part of the glandular stomach. By analyzing mutant mice with aberrant spleen development, we further demonstrate that proper formation of the gastric lobe is dependent on the initial formation of the closely positioned spleen, indicating a close interplay between pancreatic and splenic mesenchyme during development. Additionally, we show that the expression profile of markers for pancreatic multipotent progenitors within the pancreas is heterogenous with regards to lobular origin. Altogether, our studies regarding the morphogenesis and adult constitution of the mouse pancreas recognize lobular heterogeneities that add important information for future interpretations of this organ.

  • 103.
    Hörnblad, Andreas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sock, Elisabeth
    Hill, Robert
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Impaired spleen formation perturbs morphogenesis of the gastric lobe of the pancreas2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, p. e21753-Article in journal (Refereed)
    Abstract [en]

    Despite the extensive use of the mouse as a model for studies of pancreas development and disease, the development of the gastric pancreatic lobe has been largely overlooked. In this study we use optical projection tomography to provide a detailed three-dimensional and quantitative description of pancreatic growth dynamics in the mouse. Hereby, we describe the epithelial and mesenchymal events leading to the formation of the gastric lobe of the pancreas. We show that this structure forms by perpendicular growth from the dorsal pancreatic epithelium into a distinct lateral domain of the dorsal pancreatic mesenchyme. Our data support a role for spleen organogenesis in the establishment of this mesenchymal domain and in mice displaying perturbed spleen development, including Dh +/-, Bapx1-/- and Sox11-/-, gastric lobe development is disturbed. We further show that the expression profile of markers for multipotent progenitors is delayed in the gastric lobe as compared to the splenic and duodenal pancreatic lobes. Altogether, this study provides new information regarding the developmental dynamics underlying the formation of the gastric lobe of the pancreas and recognizes lobular heterogeneities regarding the time course of pancreatic cellular differentiation. Collectively, these data are likely to constitute important elements in future interpretations of the developing and/or diseased pancreas.

  • 104. Immanen, Juha
    et al.
    Nieminen, Kaisa
    Duchens Silva, Hector
    Rodriguez Rojas, Fernanda
    Meisel, Lee A.
    Silva, Herman
    Albert, Victor A.
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Helariutta, Yka
    Characterization of cytokinin signaling and homeostasis gene families in two hardwood tree species: Populus trichocarpa and Prunus persica2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 885-Article in journal (Refereed)
    Abstract [en]

    Background: Through the diversity of cytokinin regulated processes, this phytohormone has a profound impact on plant growth and development. Cytokinin signaling is involved in the control of apical and lateral meristem activity, branching pattern of the shoot, and leaf senescence. These processes influence several traits, including the stem diameter, shoot architecture, and perennial life cycle, which define the development of woody plants. To facilitate research about the role of cytokinin in regulation of woody plant development, we have identified genes associated with cytokinin signaling and homeostasis pathways from two hardwood tree species. Results: Taking advantage of the sequenced black cottonwood (Populus trichocarpa) and peach (Prunus persica) genomes, we have compiled a comprehensive list of genes involved in these pathways. We identified genes belonging to the six families of cytokinin oxidases (CKXs), isopentenyl transferases (IPTs), LONELY GUY genes (LOGs), two-component receptors, histidine containing phosphotransmitters (HPts), and response regulators (RRs). All together 85 Populus and 45 Prunus genes were identified, and compared to their Arabidopsis orthologs through phylogenetic analyses. Conclusions: In general, when compared to Arabidopsis, differences in gene family structure were often seen in only one of the two tree species. However, one class of genes associated with cytokinin signal transduction, the CKI1-like family of two-component histidine kinases, was larger in both Populus and Prunus than in Arabidopsis.

  • 105.
    Isoz, Isabelle
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Persson, Ulf
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Volkov, Kirill
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The C-terminus of Dpb2 is required for interaction with Pol2 and for cell viability2012In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 22, p. 11545-11553Article in journal (Refereed)
    Abstract [en]

    DNA polymerase ε (Pol ε) participates in the synthesis of the leading strand during DNA replication in Saccharomyces cerevisiae. Pol ε comprises four subunits: the catalytic subunit, Pol2, and three accessory subunits, Dpb2, Dpb3 and Dpb4. DPB2 is an essential gene with unclear function. A genetic screen was performed in S. cerevisiae to isolate lethal mutations in DPB2. The dpb2-200 allele carried two mutations within the last 13 codons of the open reading frame, one of which resulted in a six amino acid truncation. This truncated Dpb2 subunit was co-expressed with Pol2, Dpb3 and Dpb4 in S. cerevisiae, but this Dpb2 variant did not co-purify with the other Pol ε subunits. This resulted in the purification of a Pol2/Dpb3/Dpb4 complex that possessed high specific activity and high processivity and holoenzyme assays with PCNA, RFC and RPA on a single-primed circular template did not reveal any defects in replication efficiency. In conclusion, the lack of Dpb2 did not appear to have a negative effect on Pol ε activity. Thus, the C-terminal motif of Dpb2 that we have identified may instead be required for Dpb2 to fulfill an essential structural role at the replication origin or at the replication fork.

  • 106. Jacobs, Kevin B
    et al.
    Yeager, Meredith
    Zhou, Weiyin
    Wacholder, Sholom
    Wang, Zhaoming
    Rodriguez-Santiago, Benjamin
    Hutchinson, Amy
    Deng, Xiang
    Liu, Chenwei
    Horner, Marie-Josephe
    Cullen, Michael
    Epstein, Caroline G
    Burdett, Laurie
    Dean, Michael C
    Chatterjee, Nilanjan
    Sampson, Joshua
    Chung, Charles C
    Kovaks, Joseph
    Gapstur, Susan M
    Stevens, Victoria L
    Teras, Lauren T
    Gaudet, Mia M
    Albanes, Demetrius
    Weinstein, Stephanie J
    Virtamo, Jarmo
    Taylor, Philip R
    Freedman, Neal D
    Abnet, Christian C
    Goldstein, Alisa M
    Hu, Nan
    Yu, Kai
    Yuan, Jian-Min
    Liao, Linda
    Ding, Ti
    Qiao, You-Lin
    Gao, Yu-Tang
    Koh, Woon-Puay
    Xiang, Yong-Bing
    Tang, Ze-Zhong
    Fan, Jin-Hu
    Aldrich, Melinda C
    Amos, Christopher
    Blot, William J
    Bock, Cathryn H
    Gillanders, Elizabeth M
    Harris, Curtis C
    Haiman, Christopher A
    Henderson, Brian E
    Kolonel, Laurence N
    Le Marchand, Loic
    McNeill, Lorna H
    Rybicki, Benjamin A
    Schwartz, Ann G
    Signorello, Lisa B
    Spitz, Margaret R
    Wiencke, John K
    Wrensch, Margaret
    Wu, Xifeng
    Zanetti, Krista A
    Ziegler, Regina G
    Figueroa, Jonine D
    Garcia-Closas, Montserrat
    Malats, Nuria
    Marenne, Gaelle
    Prokunina-Olsson, Ludmila
    Baris, Dalsu
    Schwenn, Molly
    Johnson, Alison
    Landi, Maria Teresa
    Goldin, Lynn
    Consonni, Dario
    Bertazzi, Pier Alberto
    Rotunno, Melissa
    Rajaraman, Preetha
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Freeman, Laura E Beane
    Berg, Christine D
    Buring, Julie E
    Butler, Mary A
    Carreon, Tania
    Feychting, Maria
    Ahlbom, Anders
    Gaziano, J Michael
    Giles, Graham G
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Hartge, Patricia
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Inskip, Peter D
    Johansen, Christoffer
    Landgren, Annelie
    McKean-Cowdin, Roberta
    Michaud, Dominique S
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Peters, Ulrike
    Ruder, Avima M
    Sesso, Howard D
    Severi, Gianluca
    Shu, Xiao-Ou
    Visvanathan, Kala
    White, Emily
    Wolk, Alicja
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Silverman, Debra T
    Kogevinas, Manolis
    Gonzalez, Juan R
    Villa, Olaya
    Li, Donghui
    Duell, Eric J
    Risch, Harvey A
    Olson, Sara H
    Kooperberg, Charles
    Wolpin, Brian M
    Jiao, Li
    Hassan, Manal
    Wheeler, William
    Arslan, Alan A
    Bueno-de-Mesquita, H Bas
    Fuchs, Charles S
    Gallinger, Steven
    Gross, Myron D
    Holly, Elizabeth A
    Klein, Alison P
    Lacroix, Andrea
    Mandelson, Margaret T
    Petersen, Gloria
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M
    Canzian, Federico
    Chang, Kenneth
    Cotterchio, Michelle
    Giovannucci, Edward L
    Goggins, Michael
    Bolton, Judith A Hoffman
    Jenab, Mazda
    Khaw, Kay-Tee
    Krogh, Vittorio
    Kurtz, Robert C
    McWilliams, Robert R
    Mendelsohn, Julie B
    Rabe, Kari G
    Riboli, Elio
    Tjønneland, Anne
    Tobias, Geoffrey S
    Trichopoulos, Dimitrios
    Elena, Joanne W
    Yu, Herbert
    Amundadottir, Laufey
    Stolzenberg-Solomon, Rachael Z
    Kraft, Peter
    Schumacher, Fredrick
    Stram, Daniel
    Savage, Sharon A
    Mirabello, Lisa
    Andrulis, Irene L
    Wunder, Jay S
    García, Ana Patiño
    Sierrasesúmaga, Luis
    Barkauskas, Donald A
    Gorlick, Richard G
    Purdue, Mark
    Chow, Wong-Ho
    Moore, Lee E
    Schwartz, Kendra L
    Davis, Faith G
    Hsing, Ann W
    Berndt, Sonja I
    Black, Amanda
    Wentzensen, Nicolas
    Brinton, Louise A
    Lissowska, Jolanta
    Peplonska, Beata
    McGlynn, Katherine A
    Cook, Michael B
    Graubard, Barry I
    Kratz, Christian P
    Greene, Mark H
    Erickson, Ralph L
    Hunter, David J
    Thomas, Gilles
    Hoover, Robert N
    Real, Francisco X
    Fraumeni, Joseph F
    Caporaso, Neil E
    Tucker, Margaret
    Rothman, Nathaniel
    Pérez-Jurado, Luis A
    Chanock, Stephen J
    Detectable clonal mosaicism and its relationship to aging and cancer.2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 6, p. 651-658Article in journal (Refereed)
    Abstract [en]

    In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

  • 107. Jalali, Ali
    et al.
    Amirian, E. Susan
    Bainbridge, Matthew N.
    Armstrong, Georgina N.
    Liu, Yanhong
    Tsavachidis, Spyros
    Jhangiani, Shalini N.
    Plon, Sharon E.
    Lau, Ching C.
    Claus, Elizabeth B.
    Barnholtz-Sloan, Jill S.
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S.
    Jenkins, Robert B.
    Lachance, Daniel
    Olson, Sara H.
    Bernstein, Jonine L.
    Merrell, Ryan T.
    Wrensch, Margaret R.
    Davis, Faith G.
    Lai, Rose
    Shete, Sanjay
    Aldape, Kenneth
    Amos, Christopher I.
    Muzny, Donna M.
    Gibbs, Richard A.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L.
    Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8278-Article in journal (Refereed)
    Abstract [en]

    Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned.

  • 108. Jansweijer, Joeri A.
    et al.
    van Spaendonck-Zwarts, Karin Y.
    Tanck, Michael W. T.
    van Tintelen, J. Peter
    Christiaans, Imke
    van der Smagt, Jasper
    Vermeer, Alexa
    Bos, J. Martijn
    Moss, Arthur J.
    Swan, Heikki
    Priori, Sylvia
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Tfelt-Hansen, Jacob
    Ackerman, Michael
    Olivotto, Iacopo
    Charron, Philippe
    Gimeno, Juan R.
    van den Berg, Maarten
    Wilde, Arthur
    Pinto, Yigal M.
    Heritability in genetic heart disease: the role of genetic background2019In: Open heart, E-ISSN 2053-3624, Vol. 6, no 1, article id UNSP e000929Article in journal (Refereed)
    Abstract [en]

    Background: Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or ‘modifier genes’. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins.

    Methods: We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy.

    Results: Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy.

    Conclusions: Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.

  • 109.
    Janunger, Tomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    The genetic contribution to stroke in northern Sweden2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Stroke is a common multi factorial cerebrovascular disorder with a large impact on global health. It is a disorder primarily associated with old age but environmental factors, lifestyle choices and medical history are all important for the risk of developing the disorder. It is also known that heritability is important for predisposition to the disorder. The aim of this work has been to identify genetic variations that increase the risk of being affected by stroke in the population of northern Sweden, a population well apt for genetic studies due to well kept church and medical records together with limited genetic diversity.

    In the first paper we used linkage analysis in families with early onset of stroke. By this approach we identified a region on chromosome 5q to be linked to an increased risk of developing stroke, a region previously identified as a susceptibility locus for stroke in the Icelandic population. In the second study we used genealogy to identify common ancestry and thereby identify common susceptibility to stroke. The seven families we connected showed significant linkage to the chromosome 9q31-33 region and four of the families shared a common haplotype over 2.1 megabases. In the third manuscript we investigated sequence variation of two candidate genes, TNFSF15 and TLR4. Sequencing of the TLR4 gene revealed previously identified variations in affected individuals from two of the families. Further SNP analysis showed five separate haplotypes among the investigated families and four haplotypes for TNFSF15. However none of these co-segregated with stroke among the investigated families. In the final paper we used a case-control stroke cohort to ascertain association for genetic variation in five genes and genetic regions previously suggested to be linked with stroke. Initial analyses showed association for the 9p21 chromosomal region and a variant in Factor 5 that showed protection against stroke, but after adjustments for common risk factors for stroke, the findings were no longer significant.

    In conclusion, by studying selected families we have been able to show linkage to two chromosomal regions, 5q and 9q31-33, that indicate genetic predisposition for developing stroke. Further we have shown that family based studies are still an important tool in deciphering the underlying mechanisms for complex disease.

  • 110. Ji, Xuemei
    et al.
    Bosse, Yohan
    Landi, Maria Teresa
    Gui, Jiang
    Xiao, Xiangjun
    Qian, David
    Joubert, Philippe
    Lamontagne, Maxime
    Li, Yafang
    Gorlov, Ivan
    de Biasi, Mariella
    Han, Younghun
    Gorlova, Olga
    Hung, Rayjean J.
    Wu, Xifeng
    Mckay, James
    Zong, Xuchen
    Carreras-Torres, Robert
    Christiani, David C.
    Caporaso, Neil
    Johansson, Mattias
    Liu, Geoffrey
    Bojesen, Stig E.
    Le Marchand, Loic
    Albanes, Demetrios
    Bickeboeller, Heike
    Aldrich, Melinda C.
    Bush, William S.
    Tardon, Adonina
    Rennert, Gad
    Chen, Chu
    Teare, M. Dawn
    Field, John K.
    Kiemeney, Lambertus A.
    Lazarus, Philip
    Haugen, Aage
    Lam, Stephen
    Schabath, Matthew B.
    Andrew, Angeline S.
    Shen, Hongbing
    Hong, Yun-Chul
    Yuan, Jian-Min
    Bertazzi, Pier A.
    Pesatori, Angela C.
    Ye, Yuanqing
    Diao, Nancy
    Su, Li
    Zhang, Ruyang
    Brhane, Yonathan
    Leighl, Natasha
    Johansen, Jakob S.
    Mellemgaard, Anders
    Saliba, Walid
    Haiman, Christopher
    Wilkens, Lynne
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    van der Heijden, Erik H. F. M.
    Kim, Jin Hee
    Dai, Juncheng
    Hu, Zhibin
    Davies, Michael P. A.
    Marcus, Michael W.
    Brunnstrom, Hans
    Manjer, Jonas
    Melander, Olle
    Muller, David C.
    Overvad, Kim
    Trichopoulou, Antonia
    Tumino, Rosario
    Doherty, Jennifer
    Goodman, Gary E.
    Cox, Angela
    Taylor, Fiona
    Woll, Penella
    Brueske, Irene
    Manz, Judith
    Muley, Thomas
    Risch, Angela
    Rosenberger, Albert
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Shepherd, Frances
    Tsao, Ming-Sound
    Arnold, Susanne M.
    Haura, Eric B.
    Bolca, Ciprian
    Holcatova, Ivana
    Janout, Vladimir
    Kontic, Milica
    Lissowska, Jolanta
    Mukeria, Anush
    Ognjanovic, Simona
    Orlowski, Tadeusz M.
    Scelo, Ghislaine
    Swiatkowska, Beata
    Zaridze, David
    Bakke, Per
    Skaug, Vidar
    Zienolddiny, Shanbeh
    Duell, Eric J.
    Butler, Lesley M.
    Koh, Woon-Puay
    Gao, Yu-Tang
    Houlston, Richard
    McLaughlin, John
    Stevens, Victoria
    Nickle, David C.
    Obeidat, Ma'en
    Timens, Wim
    Zhu, Bin
    Song, Lei
    Artigas, Maria Soler
    Tobin, Martin D.
    Wain, Louise V.
    Gu, Fangyi
    Byun, Jinyoung
    Kamal, Ahsan
    Zhu, Dakai
    Tyndale, Rachel F.
    Wei, Wei-Qi
    Chanock, Stephen
    Brennan, Paul
    Amos, Christopher I.
    Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, p. 1-15, article id 3221Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

  • 111.
    Jia, Shaodong
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Buckland, Robert
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Determination of deoxyribonucleoside triphosphate concentrations in yeast cells by strong anion-exchange high-performance liquid chromatography coupled with ultraviolet detection2015In: DNA Replikation: Methods and Protocols / [ed] Sonya Vengrova; Jacob Dalgaard, Warwick Medical School, University of Warwick, New York: Springer-Verlag New York, 2015, Vol. 1300, p. 113-121Chapter in book (Refereed)
    Abstract [en]

    DNA polymerase assays are commonly used for the detection of deoxyribonucleoside triphosphates (dNTPs) in biological samples. For better specificity and accuracy, high-performance liquid chromatography (HPLC) methods have been developed for the analysis of the four dNTPs in complex samples. Here we describe a simple method using isocratic strong anion-exchange (SAX) chromatographic separation coupled with ultraviolet detection (UV) for the analysis of the four dNTPs in budding yeast Saccharomyces cerevisiae. This method can be applied to other species of yeast or bacteria.

  • 112. Jiang, Xia
    et al.
    Finucane, Hilary K.
    Schumacher, Fredrick R.
    Schmit, Stephanie L.
    Tyrer, Jonathan P.
    Han, Younghun
    Michailidou, Kyriaki
    Lesseur, Corina
    Kuchenbaecker, Karoline B.
    Dennis, Joe
    Conti, David V.
    Casey, Graham
    Gaudet, Mia M.
    Huyghe, Jeroen R.
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline S.
    Andrulis, Irene L.
    Anton-Culver, Hoda
    Antoniou, Antonis C.
    Antonenkova, Natalia N.
    Arnold, Susanne M.
    Aronson, Kristan J.
    Arun, Banu K.
    Bandera, Elisa V.
    Barkardottir, Rosa B.
    Barnes, Daniel R.
    Batra, Jyotsna
    Beckmann, Matthias W.
    Benitez, Javier
    Benlloch, Sara
    Berchuck, Andrew
    Berndt, Sonja I.
    Bickeboeller, Heike
    Bien, Stephanie A.
    Blomqvist, Carl
    Boccia, Stefania
    Bogdanova, Natalia V.
    Bojesen, Stig E.
    Bolla, Manjeet K.
    Brauch, Hiltrud
    Brenner, Hermann
    Brenton, James D.
    Brook, Mark N.
    Brunet, Joan
    Brunnstrom, Hans
    Buchanan, Daniel D.
    Burwinkel, Barbara
    Butzow, Ralf
    Cadoni, Gabriella
    Caldes, Trinidad
    Caligo, Maria A.
    Campbell, Ian
    Campbell, Peter T.
    Cancel-Tassin, Geraldine
    Cannon-Albright, Lisa
    Campa, Daniele
    Caporaso, Neil
    Carvalho, Andre L.
    Chan, Andrew T.
    Chang-Claude, Jenny
    Chanock, Stephen J.
    Chen, Chu
    Christiani, David C.
    Claes, Kathleen B. M.
    Claessens, Frank
    Clements, Judith
    Collee, J. Margriet
    Correa, Marcia Cruz
    Couch, Fergus J.
    Cox, Angela
    Cunningham, Julie M.
    Cybulski, Cezary
    Czene, Kamila
    Daly, Mary B.
    defazio, Anna
    Devilee, Peter
    Diez, Orland
    Gago-Dominguez, Manuela
    Donovan, Jenny L.
    Doerk, Thilo
    Duell, Eric J.
    Dunning, Alison M.
    Dwek, Miriam
    Eccles, Diana M.
    Edlund, Christopher K.
    Edwards, Digna R. Velez
    Ellberg, Carolina
    Evans, D. Gareth
    Fasching, Peter A.
    Ferris, Robert L.
    Liloglou, Triantafillos
    Figueiredo, Jane C.
    Fletcher, Olivia
    Fortner, Renee T.
    Fostira, Florentia
    Franceschi, Silvia
    Friedman, Eitan
    Gallinger, Steven J.
    Ganz, Patricia A.
    Garber, Judy
    Garcia-Saenz, Jose A.
    Gayther, Simon A.
    Giles, Graham G.
    Godwin, Andrew K.
    Goldberg, Mark S.
    Goldgar, David E.
    Goode, Ellen L.
    Goodman, Marc T.
    Goodman, Gary
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Greene, Mark H.
    Gronberg, Henrik
    Gronwald, Jacek
    Guenel, Pascal
    Hakansson, Niclas
    Hall, Per
    Hamann, Ute
    Hamdy, Freddie C.
    Hamilton, Robert J.
    Hampe, Jochen
    Haugen, Aage
    Heitz, Florian
    Herrero, Rolando
    Hillemanns, Peter
    Hoffmeister, Michael
    Hogdall, Estrid
    Hong, Yun-Chul
    Hopper, John L.
    Houlston, Richard
    Hulick, Peter J.
    Hunter, David J.
    Huntsman, David G.
    Idos, Gregory
    Imyanitov, Evgeny N.
    Ingles, Sue Ann
    Isaacs, Claudine
    Jakubowska, Anna
    James, Paul
    Jenkins, Mark A.
    Johansson, Mattias
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    John, Esther M.
    Joshi, Amit D.
    Kaneva, Radka
    Karlan, Beth Y.
    Kelemen, Linda E.
    Kuhl, Tabea
    Khaw, Kay-Tee
    Khusnutdinova, Elza
    Kibel, Adam S.
    Kiemeney, Lambertus A.
    Kim, Jeri
    Kjaer, Susanne K.
    Knight, Julia A.
    Kogevinas, Manolis
    Kote-Jarai, Zsofia
    Koutros, Stella
    Kristensen, Vessela N.
    Kupryjanczyk, Jolanta
    Lacko, Martin
    Lam, Stephan
    Lambrechts, Diether
    Landi, Maria Teresa
    Lazarus, Philip
    Le, Nhu D.
    Lee, Eunjung
    Lejbkowicz, Flavio
    Lenz, Heinz-Josef
    Leslie, Goska
    Lessel, Davor
    Lester, Jenny
    Levine, Douglas A.
    Li, Li
    Li, Christopher I.
    Lindblom, Annika
    Lindor, Noralane M.
    Liu, Geoffrey
    Loupakis, Fotios
    Lubinski, Jan
    Maehle, Lovise
    Maier, Christiane
    Mannermaa, Arto
    Le Marchand, Loic
    Margolin, Sara
    May, Taymaa
    McGuffog, Lesley
    Meindl, Alfons
    Middha, Pooja
    Miller, Austin
    Milne, Roger L.
    MacInnis, Robert J.
    Modugno, Francesmary
    Montagna, Marco
    Moreno, Victor
    Moysich, Kirsten B.
    Mucci, Lorelei
    Muir, Kenneth
    Mulligan, Anna Marie
    Nathanson, Katherine L.
    Neal, David E.
    Ness, Andrew R.
    Neuhausen, Susan L.
    Nevanlinna, Heli
    Newcomb, Polly A.
    Newcomb, Lisa F.
    Nielsen, Finn Cilius
    Nikitina-Zake, Liene
    Nordestgaard, Borge G.
    Nussbaum, Robert L.
    Offit, Kenneth
    Olah, Edith
    Al Olama, Ali Amin
    Olopade, Olufunmilayo I.
    Olshan, Andrew F.
    Olsson, Hakan
    Osorio, Ana
    Pandha, Hardev
    Park, Jong Y.
    Pashayan, Nora
    Parsons, Michael T.
    Pejovic, Tanja
    Penney, Kathryn L.
    Peters, Wilbert H. M.
    Phelan, Catherine M.
    Phipps, Amanda I.
    Plaseska-Karanfilska, Dijana
    Pring, Miranda
    Prokofyeva, Darya
    Radice, Paolo
    Stefansson, Kari
    Ramus, Susan J.
    Raskin, Leon
    Rennert, Gad
    Rennert, Hedy S.
    van Rensburg, Elizabeth J.
    Riggan, Marjorie J.
    Risch, Harvey A.
    Risch, Angela
    Roobol, Monique J.
    Rosenstein, Barry S.
    Rossing, Mary Anne
    De Ruyck, Kim
    Saloustros, Emmanouil
    Sandler, Dale P.
    Sawyer, Elinor J.
    Schabath, Matthew B.
    Schleutker, Johanna
    Schmidt, Marjanka K.
    Setiawan, V. Wendy
    Shen, Hongbing
    Siegel, Erin M.
    Sieh, Weiva
    Singer, Christian F.
    Slattery, Martha L.
    Sorensen, Karina Dalsgaard
    Southey, Melissa C.
    Spurdle, Amanda B.
    Stanford, Janet L.
    Stevens, Victoria L.
    Stintzing, Sebastian
    Stone, Jennifer
    Sundfeldt, Karin
    Sutphen, Rebecca
    Swerdlow, Anthony J.
    Tajara, Eloiza H.
    Tangen, Catherine M.
    Tardon, Adonina
    Taylor, Jack A.
    Teare, M. Dawn
    Teixeira, Manuel R.
    Terry, Mary Beth
    Terry, Kathryn L.
    Thibodeau, Stephen N.
    Thomassen, Mads
    Bjorge, Line
    Tischkowitz, Marc
    Toland, Amanda E.
    Torres, Diana
    Townsend, Paul A.
    Travis, Ruth C.
    Tung, Nadine
    Tworoger, Shelley S.
    Ulrich, Cornelia M.
    Usmani, Nawaid
    Vachon, Celine M.
    Van Nieuwenhuysen, Els
    Vega, Ana
    Aguado-Barrera, Miguel Elias
    Wang, Qin
    Webb, Penelope M.
    Weinberg, Clarice R.
    Weinstein, Stephanie
    Weissler, Mark C.
    Weitzel, Jeffrey N.
    West, Catharine M. L.
    White, Emily
    Whittemore, Alice S.
    Wichmann, H-Erich
    Wiklund, Fredrik
    Winqvist, Robert
    Wolk, Alicja
    Woll, Penella
    Woods, Michael
    Wu, Anna H.
    Wu, Xifeng
    Yannoukakos, Drakoulis
    Zheng, Wei
    Zienolddiny, Shanbeh
    Ziogas, Argyrios
    Zorn, Kristin K.
    Lane, Jacqueline M.
    Saxena, Richa
    Thomas, Duncan
    Hung, Rayjean J.
    Diergaarde, Brenda
    Mckay, James
    Peters, Ulrike
    Hsu, Li
    Garcia-Closas, Montserrat
    Eeles, Rosalind A.
    Chenevix-Trench, Georgia
    Brennan, Paul J.
    Haiman, Christopher A.
    Simard, Jacques
    Easton, Douglas F.
    Gruber, Stephen B.
    Pharoah, Paul D. P.
    Price, Alkes L.
    Pasaniuc, Bogdan
    Amos, Christopher I.
    Kraft, Peter
    Lindstrom, Sara
    Shared heritability and functional enrichment across six solid cancers2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 431Article in journal (Refereed)
    Abstract [en]

    Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

  • 113.
    Johansson, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Dixon, Nicholas
    Replicative DNA polymerases2013In: Cold Spring Harbor Perspectives in Biology, ISSN 1943-0264, E-ISSN 1943-0264, Vol. 5, no 6, p. a012799-Article in journal (Refereed)
    Abstract [en]

    In 1959, Arthur Kornberg was awarded the Nobel Prize for his work on the principles by which DNA is duplicated by DNA polymerases. Since then, it has been confirmed in all branches of life that replicative DNA polymerases require a single-stranded template to build a complementary strand, but they cannot start a new DNA strand de novo. Thus, they also depend on a primase, which generally assembles a short RNA primer to provide a 3'-OH that can be extended by the replicative DNA polymerase. The general principles that (1) a helicase unwinds the double-stranded DNA, (2) single-stranded DNA-binding proteins stabilize the single-stranded DNA, (3) a primase builds a short RNA primer, and (4) a clamp loader loads a clamp to (5) facilitate the loading and processivity of the replicative polymerase, are well conserved among all species. Replication of the genome is remarkably robust and is performed with high fidelity even in extreme environments. Work over the last decade or so has confirmed (6) that a common two-metal ion-promoted mechanism exists for the nucleotidyltransferase reaction that builds DNA strands, and (7) that the replicative DNA polymerases always act as a key component of larger multiprotein assemblies, termed replisomes. Furthermore (8), the integrity of replisomes is maintained by multiple protein-protein and protein-DNA interactions, many of which are inherently weak. This enables large conformational changes to occur without dissociation of replisome components, and also means that in general replisomes cannot be isolated intact.

  • 114. Johansson, J.
    et al.
    Berg, T.
    Kurzejamska, E.
    Pang, M-F
    Tabor, V.
    Jansson, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Roswall, P.
    Pietras, K.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Religa, P.
    Fuxe, J.
    MiR-155-mediated loss of C/EBP beta shifts the TGF-beta response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer2013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 50, p. 5614-5624Article in journal (Refereed)
    Abstract [en]

    During breast cancer progression, transforming growth factor-beta (TGF-beta) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBP beta), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-beta-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBP beta was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBP beta potentiated the TGF-beta response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-beta. Furthermore, loss of C/EBP beta enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBP beta promoted the TGF-beta response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBP beta as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBP beta as a mechanism, which promotes breast cancer progression by shifting the TGF-beta response from growth inhibition to EMT, invasion and metastasis.

  • 115.
    Johansson, Jenni
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Sandgren, Ola
    Brice, Alexis
    Holmgren, Gösta
    Holmberg, Monica
    Expanded CAG repeats in Swedish Spinocerebellar ataxia type 7 (SCA7) patients: effect of repeat length on the clinical manifestation1998In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 7, no 2, p. 171-176Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. The gene responsible for SCA7, located on chromosome 3p, recently was cloned and shown to contain a CAG repeat in the coding region of the gene, that is expanded in SCA7 patients of French origin, We examined the SCA7 repeat region in four Swedish SCA7 families as well as in 57 healthy controls, All Swedish SCA7 patients exhibited expanded CAG repeats with a strong negative correlation between repeat size and age of onset, The repeat length in SCA7 patients ranged from 40 to >200 repeats, The largest expansion was observed in a juvenile case with an age of onset of 3 months, and represents the longest polyglutamine stretch ever reported, In patients with 59 repeats or more, visual impairment was the most common initial symptom observed, while ataxia predominates in patients with <59 repeats. Two of the Swedish SCA7 families analysed in this study were shown to be related genealogically, The other two SCA7 families could not be traced back to a common ancestor, All four families shared the same allele on the disease chromosome at a locus closely linked to SCA7, suggesting the possibility of a founder effect in the Swedish population.

  • 116.
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Genetic and Molecular analysis of the Spinocerebellar ataxia type 7 (SCA7) disease gene2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a hereditary neurodegenerative disorder affecting the cerebellum, pons and retina. SCA7 patients present with gait ataxia and visual impairment as the main symptoms. Anticipation, commonly observed in SCA7 families, is a phenomenon where an earlier age at onset and a more severe progression of disease is seen in successive generations.

    In order to identify the gene responsible for SCA7, we performed linkage analysis on a Swedish SCA7 kindred. Evidence for linkage of the SCA7 disease locus to a 32 cM region on chromosome 3p12-21.1, between markers D3S1547 and D3S1274, was established.

    A number of neurodegenerative disorders associated with anticipation are caused by expanded (CAG)n repeats in their respective disease genes. In order to isolate the SCA7 disease gene we, therefore, screened a human infant brain stem cDNA library for CAG repeat containing clones, mapping to chromosome 3. Four candidate clones were isolated and analysed, but could all be excluded as the SCA7 disease gene.

    In 1997, the SCA7 disease gene was identified and, as expected, shown to harbour a CAG repeat, expanded in SCA7 patients. Analysis of the SCA7 CAG repeat region in Swedish SCA7 patients demonstrated that CAG repeat size was negatively correlated to age at onset of disease. Furthermore, patients with larger repeats presented with visual impairment, whereas patients with smaller repeats presented with ataxia as the initial symptom.

    SCA7 is the most common autosomal dominant cerebellar ataxia in Sweden and Finland, but rare in other populations. In order to investigate if the relatively high frequency of SCA7 in these countries is the result of a founder effect in the region, a haplotype analysis was performed on all SCA7 families available. All

    7 families shared a common haplotype of at least 1.9 cM surrounding the SCA7 locus. In addition, strong linkage disequilibrium was demonstrated for marker D3S1287 closely linked to the SCA7 gene, suggesting a founder effect for the SCA7 mutation in Sweden and Finland.

    The function of the SCA7 protein, ataxin-7, is not known and it does not show significant homologies to any previously known proteins. In order to gain insight into the function of ataxin-7 we analysed the expression of ataxin-7 in brain and peripheral tissue from SCA7 patients and controls. In brain, expression was found to be mainly neuronal with a nuclear subcellular localisation. Ataxin-7 expression was found throughout the CNS, not restricted to sites of pathology. We also confirmed previously reported findings of neuronal intranuclear inclusions (NIls) in the brains of SCA7 patients. Based on our findings, we conclude that the cell type specific neurodegeneration in SCA7 is not due to differences in expression pattern in affected and non-affected tissue or the distribution pattern of aggregated protein.

  • 117.
    Jonasson, Jenni
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Juvonen, Vesa
    Sistonen, Pertti
    Ignatius, Jaakko
    Johansson, Daniel
    Björk, Erik
    Wahlström, Jan
    Melberg, Atle
    Holmgren, Gösta
    Forsgren, Lars
    Holmberg, Monica
    Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia2000In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 8, no 12, p. 918-922Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCAI gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.

  • 118. Jonasson, Jenni
    et al.
    Ström, Anna-Lena
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hart, Patricia
    Brännström, Thomas
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Holmberg, Monica
    Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals2002In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, no 1, p. 29-37Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.

  • 119.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Burstedt, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Kellgren, Therese
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa2018In: Molecular Vision, ISSN 1090-0535, E-ISSN 1090-0535, Vol. 24, p. 667-678Article in journal (Refereed)
    Abstract [en]

    Purpose: Retinitis pigmentosa (RP) represents a large group of inherited retinal diseases characterized by clinical and genetic heterogeneity. Among patients with RP in northern Sweden, we identified two severely affected siblings and aimed to reveal a genetic cause underlying their disease.

    Methods: Whole exome sequencing (WES) was performed on both affected individuals. Sequence variants were filtered using a custom pipeline to find a rare or novel variant predicted to affect protein function. Genome-wide genotyping was used to identify copy number variants (CNVs) and homozygous regions with potential disease causative genes.

    Results: WES uncovered a novel heterozygous variant in the MER proto-oncogene, tyrosine kinase (MERTK) gene, c.2309A>G, p.Glu770Gly located in the tyrosine kinase domain and predicted to be likely pathogenic. The second variant, a large heterozygous deletion encompassing exons 1 to 7 of the MERTK gene, was revealed with genome-wide genotyping. The CNV analysis suggested breakpoints of the deletion, in the 5′-untranslated region and in intron 7. We identified genomic sequences at the site of the deletion as part of L1ME4b (LINE/L1) and AluSx3 that indicated a non-homologous recombination as a mechanism of the deletion evolvement.

    Conclusions: Patients with RP in this study were carriers of two novel allelic mutations in the MERTK gene, a missense variant in exon 17 and an approximate 91 kb genomic deletion. Mapping of the deletion breakpoints allowed molecular testing of a cohort of patients with RP with allele-specific PCR. These findings provide additional information about mutations in MERTK for molecular testing of unsolved recessive RP cases and highlight the necessity for analysis of large genomic deletions.

  • 120.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Burstedt, Marie S
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 11, p. 1266-1271Article in journal (Refereed)
    Abstract [en]

    This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

  • 121. Jose Ariza, Maria
    et al.
    Luis Martinez-Hernandez, Pedro
    Ibarretxe, Daiana
    Rabacchi, Claudio
    Rioja, Jose
    Grande-Aragon, Cristina
    Plana, Nuria
    Tarugi, Patrizia
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Calandra, Sebastiano
    Valdivielso, Pedro
    Novel mutations in the GPIHBP1 gene identified in 2 patients with recurrent acute pancreatitis2016In: Journal of Clinical Lipidology, ISSN 1933-2874, E-ISSN 1876-4789, Vol. 10, no 1, p. 92-100Article in journal (Refereed)
    Abstract [en]

    Background: Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) has been demonstrated to be essential for the in vivo function of lipoprotein lipase (LPL), the major triglyceride (TG)-hydrolyzing enzyme involved in the intravascular lipolysis of TG-rich lipoproteins. Recently, loss-of-function mutations ofGPIHBP1 have been reported as the cause of type I hyperlipoproteinemia in several patients.

    Methods: Two unrelated patients were referred to our Lipid Units because of a severe hypertriglyceridemia and recurrent pancreatitis. We measured LPL activity in postheparin plasma and serum ApoCII and sequenced LPLAPOC2, and GPIHBP1.

    Results: The 2 patients exhibited very low LPL activity not associated with mutations in LPL gene or with ApoCII deficiency. The sequence of GPIHBP1 revealed 2 novel point mutations. One patient (proband 1) was found to be homozygous for a C>A transversion in exon 3 resulting in the conversion of threonine to lysine at position 80 (p.Thr80Lys). The other patient (proband 2) was found to be homozygous for a G>T transversion in the third base of the ATG translation initiation codon in exon 1, resulting in the conversion of methionine to isoleucine (p.Met1Ile).

    Conclusion: In conclusion, we have identified 2 novel GPIHBP1 missense mutations in 2 unrelated patients as the cause of their severe hypertriglyceridemia.

  • 122. Justice, Anne E.
    et al.
    Karaderi, Tugce
    Highland, Heather M.
    Young, Kristin L.
    Graff, Mariaelisa
    Lu, Yingchang
    Turcot, Valerie
    Auer, Paul L.
    Fine, Rebecca S.
    Guo, Xiuqing
    Schurmann, Claudia
    Lempradl, Adelheid
    Marouli, Eirini
    Mahajan, Anubha
    Winkler, Thomas W.
    Locke, Adam E.
    Medina-Gomez, Carolina
    Esko, Tonu
    Vedantam, Sailaja
    Giri, Ayush
    Lo, Ken Sin
    Alfred, Tamuno
    Mudgal, Poorva
    Ng, Maggie C. Y.
    Heard-Costa, Nancy L.
    Feitosa, Mary F.
    Manning, Alisa K.
    Willems, Sara M.
    Sivapalaratnam, Suthesh
    Abecasis, Goncalo
    Alam, Dewan S.
    Allison, Matthew
    Amouyel, Philippe
    Arzumanyanm, Zorayr
    Balkau, Beverley
    Bastarache, Lisa
    Bergmann, Sven
    Bielak, Lawrence F.
    Blueher, Matthias
    Boehnke, Michael
    Boeing, Heiner
    Boerwinkle, Eric
    Boeger, Carsten A.
    Bork-Jensen, Jette
    Bottinger, Erwin P.
    Bowden, Donald W.
    Brandslund, Ivan
    Broer, Linda
    Burt, Amber A.
    Butterworth, Adam S.
    Caulfield, Markj
    Cesana, Giancarlo
    Chambers, John C.
    Chasman, Daniel, I
    Chen, Yii-Der Ida
    Chowdhury, Rajiv
    Christensen, Cramer
    Chu, Audreyy
    Collins, Francis S.
    Cook, James P.
    Cox, Amanda J.
    Crosslin, David S.
    Danesh, John
    de Bakker, Paul I. W.
    de Denus, Simon
    de Mutsert, Renee
    Dedoussis, George
    Demerath, Ellen W.
    Dennis, Joe G.
    Denny, Josh C.
    Di Angelantonio, Emanuele
    Doerr, Marcus
    Drenos, Fotios
    Dube, Marie-Pierre
    Dunning, Alison M.
    Easton, Douglas F.
    Elliott, Paul
    Evangelou, Evangelos
    Farmaki, Aliki-Eleni
    Feng, Shuang
    Ferrannini, Ele
    Ferrieres, Jean
    Florez, Jose C.
    Fornage, Myriam
    Fox, Caroline S.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmo, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Friedrich, Nele
    Gan, Wei
    Gandin, Ilaria
    Gasparini, Paolo
    Giedraitis, Vilmantas
    Girotto, Giorgia
    Gorski, Mathias
    Grallert, Harald
    Grarup, Niels
    Groves, Megan L.
    Gustafsson, Stefan
    Haessler, Jeff
    Hansen, Torben
    Hattersley, Andrew T.
    Hayward, Caroline
    Heid, Iris M.
    Holmen, Oddgeir L.
    Hovingh, G. Kees
    Howson, Joanna M. M.
    Hu, Yao
    Hung, Yi-Jen
    Hveem, Kristian
    Ikram, M. Arfan
    Ingelsson, Erik
    Jackson, Anne U.
    Jarvik, Gail P.
    Jia, Yucheng
    Jorgensen, Torben
    Jousilahti, Pekka
    Justesen, Johanne M.
    Kahali, Bratati
    Karaleftheri, Maria
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kee, Frank
    Kitajima, Hidetoshi
    Komulainen, Pirjo
    Kooner, Jaspal S.
    Kovacs, Peter
    Kraemer, Bernhard K.
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Laakso, Markku
    Lakka, Timo A.
    Lamparter, David
    La Nge, Leslie A.
    Langenberg, Claudia
    Larson, Eric B.
    Lee, Nanette R.
    Lee, Wen-Jane
    Lehtimaeki, Terho
    Lewis, Cora E.
    Li, Huaixing
    Li, Jin
    RuifangLi-Gao,
    Lin, Li-An
    Lin, Xu
    Lind, Lars
    Lindstroem, Jaana
    Linneberg, Allan
    Liu, Ching-Ti
    Liu, Dajiang J.
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    MacGregor, Stuart
    Magi, Reedik
    Mannisto, Satu
    Marenne, Gaelle
    Marten, Jonathan
    Mascal, Nicholas G. D.
    McCarthy, Mark, I
    Meidtner, Karina
    Mihailov, Evelin
    Moilanen, Leena
    Moitry, Marie
    Mook-Kanamori, Dennis O.
    Morgan, Anna
    Morris, Andrew P.
    Mueller-Nurasyid, Martina
    Munroe, Patricia B.
    Narisu, Narisu
    Nelson, Christopher P.
    Neville, Matt
    Ntalla, Ioanna
    Owen, Katharine R.
    Pedersen, Oluf
    Peloso, Gina M.
    Pennell, Craig E.
    Perola, Markus
    James, A.
    Perry, John R. B.
    Pers, Tune H.
    Ewing, Ailith
    Polasek, Ozren
    Rasheed, Asif
    Raulerson, Chelsea K.
    Rauramaa, Rainer
    Reilly, Dermot F.
    Reiner, Alex P.
    Ridker, Paul M.
    Rivas, Manuel A.
    Robertson, Neil R.
    Robino, Antonietta
    Rudan, Igor
    Ruth, Katherine S.
    Saleheen, Danish
    Salomaa, Veikko
    Samani, Nilesh J.
    Schreiner, Pamela J.
    Schulze, Matthias B.
    Scott, Robert A.
    Segura-Lepe, Marcelo
    Sim, Xueling
    Slater, Andrew J.
    Small, Kerrin S.
    Smith, Blair H.
    Smith, Jennifer A.
    Southam, Lorraine
    Spector, Timothy D.
    Speliotes, Elizabeth K.
    Stefansson, Kari
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen E.
    Strauch, Konstantin
    Stringham, Heather M.
    Stumvoll, Michael
    Sun, Liang
    Surendran, Praveen
    Swart, Karin M. A.
    Tardif, Jean-Claude
    Taylor, Kent D.
    Teumer, Alexander
    Thompson, Deborah J.
    Thorleifsson, Gudmar
    Thorsteinsdottir, Unnur
    Thuesen, Betina H.
    Toenjes, Anke
    Torres, Mina
    Tsafantakis, Emmanouil
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    Uusitupa, Matti
    van Duijn, Cornelia M.
    Vanhala, Mauno
    Varma, Rohit
    Vermeulen, Sita H.
    Vestergaard, Henrik
    Vitart, Veronique
    Vogt, Thomas F.
    Vuckovic, Dragana
    Wagenknecht, Lynne E.
    Walker, Mark
    Wallentin, Lars
    Wang, Feijie
    Wang, Carol A.
    Wang, Shuai
    Wareham, N. Icholas J.
    Warren, Helen R.
    Waterworth, Dawn M.
    Wessel, Jennifer
    White, Harvey D.
    Willer, Cristen J.
    Wilson, James G.
    Wood, Andrew R.
    Wu, Ying
    Yaghootkar, Hanieh
    Yao, Jie
    Verges-Armstrong, Laura M.
    Young, Robin
    Zeggini, Eleftheria
    Zhan, Xiaowei
    Zhang, Weihua
    Zhao, Jing Hua
    Zhao, Wei
    Zheng, He
    Zhou, Wei
    Zillikens, M. Carola
    Rivadeneira, Fernando
    Borecki, Ingrid B.
    Pospisilik, J. Andrew
    Deloukas, Panos
    Frayling, Timothy M.
    Lettre, Guillaume
    Mohlke, Karen L.
    Rotter, Jerome, I
    Kutalik, Zoltan
    Hirschhorn, Joel N.
    Cupples, L. Adrienne
    Loos, Ruth J. F.
    North, Kari E.
    Lindgren, Cecilia M.
    O'Connell, Jeffrey R.
    Raitakari, Olli T.
    Lange, Leslie A.
    Uitterlinden, Andr G.
    Grove, Megan L.
    Masca, Nicholas G. D.
    Luan, Jianan
    Wareham, Nicholas J.
    Esko, Tnu
    De Bakker, Paul Iw
    Caulfield, Mark J.
    Mller-Nurasyid, Martina
    Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 452-469Article in journal (Refereed)
    Abstract [en]

    Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

  • 123.
    Kaati, Gunnar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bygren, Lars Olov
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Pembrey, Marcus
    Sjöstrom, Michael
    Transgenerational response to nutrition, early life circumstances and longevity2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 7, p. 784-790Article in journal (Refereed)
    Abstract [en]

    Nutrition might induce, at some loci, epigenetic or other changes that could be transmitted to the next generation impacting on health. The slow growth period (SGP) before the prepubertal peak in growth velocity has emerged as a sensitive period where different food availability is followed by different transgenerational response (TGR). The aim of this study is to investigate to what extent the probands own childhood circumstances are in fact the determinants of the findings. In the analysis, data from three random samples, comprising 271 probands and their 1626 parents and grandparents, left after exclusions because of missing data, were utilized. The availability of food during any given year was classified based on regional statistics. The ancestors' SGP was set at the ages of 8-12 years and the availability of food during these years classified as good, intermediate or poor. The probands' childhood circumstances were defined by the father's ownership of land, the number of siblings and order in the sibship, the death of parents and the parents' level of literacy. An earlier finding of a sex-specific influence from the ancestors' nutrition during the SGP, going from the paternal grandmother to the female proband and from the paternal grandfather to the male proband, was confirmed. In addition, a response from father to son emerged when childhood social circumstances of the son were accounted for. Early social circumstances influenced longevity for the male proband. TGRs to ancestors' nutrition prevailed as the main influence on longevity.

  • 124. Kapferer-Seebacher, Ines
    et al.
    Pepin, Melanie
    Werner, Roland
    Aitman, Timothy J
    Nordgren, Ann
    Stoiber, Heribert
    Thielens, Nicole
    Gaboriaud, Christine
    Amberger, Albert
    Schossig, Anna
    Gruber, Robert
    Giunta, Cecilia
    Bamshad, Michael
    Björck, Erik
    Chen, Christina
    Chitayat, David
    Dorschner, Michael
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Hale, Christopher J
    Hanna, David
    Hennies, Hans Christian
    Heiss-Kisielewsky, Irene
    Lindstrand, Anna
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Mitchell, Anna L
    Nickerson, Deborah A
    Reinstein, Eyal
    Rohrbach, Marianne
    Romani, Nikolaus
    Schmuth, Matthias
    Silver, Rachel
    Taylan, Fulya
    Vandersteen, Anthony
    Vandrovcova, Jana
    Weerakkody, Ruwan
    Yang, Margaret
    Pope, F Michael
    Byers, Peter H
    Zschocke, Johannes
    Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, no 5, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

  • 125. Karrman, Kristina
    et al.
    Castor, Anders
    Behrendtz, Mikael
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Olsson, Linda
    Ehinger, Mats
    Biloglav, Andrea
    Fioretos, Thoas
    Paulsson, Kajsa
    Johansson, Bertil
    Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A2015In: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 8, article id 42Article in journal (Refereed)
    Abstract [en]

    Background: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations, subsequently giving rise to a malignant, clonal expansion of T-lymphoblasts. The aim of the present study was to identify additional as well as cooperative genetic events in T-ALL.

    Methods: A population-based pediatric T-ALL series comprising 47 cases was investigated by SNP array and deep sequencing analyses of 75 genes, in order to ascertain pathogenetically pertinent aberrations and to identify cooperative events.

    Results: The majority (92%) of cases harbored copy number aberrations/uniparental isodisomies (UPIDs), with a median of three changes (range 0-11) per case. The genes recurrently deleted comprised CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. No case had a whole chromosome UPID; in fact, literature data show that this is a rare phenomenon in T-ALL. However, segmental UPIDs (sUPIDs) were seen in 42% of our cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes sequenced, 14 (19%) were mutated in 28 (72%) of 39 analyzed cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse; thus, such mutations can be secondary events.

    Conclusions: Deep sequencing and SNP array analyses of T-ALL revealed lack of wUPIDs, a high proportion of sUPID9p targeting CDKN2A, NOTCH1 mutations in subclones, and recurrent mutations of genes involved in signaling transduction, epigenetic regulation, and transcription.

  • 126. Kato, Norihiro
    et al.
    Loh, Marie
    Takeuchi, Fumihiko
    Verweij, Niek
    Wang, Xu
    Zhang, Weihua
    Kelly, Tanika N.
    Saleheen, Danish
    Lehne, Benjamin
    Leach, Irene Mateo
    Drong, Alexander W.
    Abbott, James
    Wahl, Simone
    Tan, Sian-Tsung
    Scott, William R.
    Campanella, Gianluca
    Chadeau-Hyam, Marc
    Afzal, Uzma
    Ahluwalia, Tarunveer S.
    Bonder, Marc Jan
    Chen, Peng
    Dehghan, Abbas
    Edwards, Todd L.
    Esko, Tonu
    Go, Min Jin
    Harris, Sarah E.
    Hartiala, Jaana
    Kasela, Silva
    Kasturiratne, Anuradhani
    Khor, Chiea-Chuen
    Kleber, Marcus E.
    Li, Huaixing
    Mok, Zuan Yu
    Nakatochi, Masahiro
    Sapari, Nur Sabrina
    Saxena, Richa
    Stewart, Alexandre F. R.
    Stolk, Lisette
    Tabara, Yasuharu
    Teh, Ai Ling
    Wu, Ying
    Wu, Jer-Yuarn
    Zhang, Yi
    Aits, Imke
    Alves, Alexessander Da Silva Couto
    Das, Shikta
    Dorajoo, Rajkumar
    Hopewell, Jemma C.
    Kim, Yun Kyoung
    Koivula, Robert W.
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    Nguyen, Quang N.
    Pereira, Mark A.
    Postmus, Iris
    Raitakari, Olli T.
    Bryan, Molly Scannell
    Scott, Robert A.
    Sorice, Rossella
    Tragante, Vinicius
    Traglia, Michela
    White, Jon
    Yamamoto, Ken
    Zhang, Yonghong
    Adair, Linda S.
    Ahmed, Alauddin
    Akiyama, Koichi
    Asif, Rasheed
    Aung, Tin
    Barroso, Ines
    Bjonnes, Andrew
    Braun, Timothy R.
    Cai, Hui
    Chang, Li-Ching
    Chen, Chien-Hsiun
    Cheng, Ching-Yu
    Chong, Yap-Seng
    Collins, Rory
    Courtney, Regina
    Davies, Gail
    Delgado, Graciela
    Do, Loi D.
    Doevendans, Pieter A.
    Gansevoort, Ron T.
    Gao, Yu-Tang
    Grammer, Tanja B.
    Grarup, Niels
    Grewal, Jagvir
    Gu, Dongfeng
    Wander, Gurpreet S.
    Hartikainen, Anna-Liisa
    Hazen, Stanley L.
    He, Jing
    Heng, Chew-Kiat
    Hixson, James E.
    Hofman, Albert
    Hsu, Chris
    Huang, Wei
    Husemoen, Lise L. N.
    Hwang, Joo-Yeon
    Ichihara, Sahoko
    Igase, Michiya
    Isono, Masato
    Justesen, Johanne M.
    Katsuy, Tomohiro
    Kibriya, Muhammad G.
    Kim, Young Jin
    Kishimoto, Miyako
    Koh, Woon-Puay
    Kohara, Katsuhiko
    Kumari, Meena
    Kwek, Kenneth
    Lee, Nanette R.
    Lee, Jeannette
    Liao, Jiemin
    Lieb, Wolfgang
    Liewald, David C. M.
    Matsubara, Tatsuaki
    Matsushita, Yumi
    Meitinger, Thomas
    Mihailov, Evelin
    Milani, Lili
    Mills, Rebecca
    Mononen, Nina
    Mueller-Nurasyid, Martina
    Nabika, Toru
    Nakashima, Eitaro
    Ng, Hong Kiat
    Nikus, Kjell
    Nutile, Teresa
    Ohkubo, Takayoshi
    Ohnaka, Keizo
    Parish, Sarah
    Paternoster, Lavinia
    Peng, Hao
    Peters, Annette
    Pham, Son T.
    Pinidiyapathirage, Mohitha J.
    Rahman, Mahfuzar
    Rakugi, Hiromi
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Rozario, Michelle Ann
    Ruggiero, Daniela
    Sala, Cinzia F.
    Sarju, Ralhan
    Shimokawa, Kazuro
    Snieder, Harold
    Sparso, Thomas
    Spiering, Wilko
    Starr, John M.
    Stott, David J.
    Stram, Daniel O.
    Sugiyama, Takao
    Szymczak, Silke
    Tang, W. H. Wilson
    Tong, Lin
    Trompet, Stella
    Turjanmaa, Vaino
    Ueshima, Hirotsugu
    Uitterlinden, Andre G.
    Umemura, Satoshi
    Vaarasmaki, Marja
    van Dam, Rob M.
    van Gilst, Wiek H.
    van Veldhuisen, Dirk J.
    Viikari, Jorma S.
    Waldenberger, Melanie
    Wang, Yiqin
    Wang, Aili
    Wilson, Rory
    Wong, Tien-Yin
    Xiang, Yong-Bing
    Yamaguchi, Shuhei
    Ye, Xingwang
    Young, Robin D.
    Young, Terri L.
    Yuan, Jian-Min
    Zhou, Xueya
    Asselbergs, Folkert W.
    Ciullo, Marina
    Clarke, Robert
    Deloukas, Panos
    Franke, Andre
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.
    Franks, Steve
    Friedlander, Yechiel
    Gross, Myron D.
    Guo, Zhirong
    Hansen, Torben
    Jarvelin, Marjo-Riitta
    Jorgensen, Torben
    Jukema, J. Wouter
    Kahonen, Mika
    Kajio, Hiroshi
    Kivimaki, Mika
    Lee, Jong-Young
    Lehtimaki, Terho
    Linneberg, Allan
    Miki, Tetsuro
    Pedersen, Oluf
    Samani, Nilesh J.
    Sorensen, Thorkild I. A.
    Takayanagi, Ryoichi
    Toniolo, Daniela
    Ahsan, Habibul
    Allayee, Hooman
    Chen, Yuan-Tsong
    Danesh, John
    Deary, Ian J.
    Franco, Oscar H.
    Franke, Lude
    Heijman, Bastiaan T.
    Holbrook, Joanna D.
    Isaacs, Aaron
    Kim, Bong-Jo
    Lin, Xu
    Liu, Jianjun
    Maerz, Winfried
    Metspalu, Andres
    Mohlke, Karen L.
    Sanghera, Dharambir K.
    Shu, Xiao-Ou
    van Meurs, Joyce B. J.
    Vithana, Eranga
    Wickremasinghe, Ananda R.
    Wijmenga, Cisca
    Wolffenbuttel, Bruce H. W.
    Yokota, Mitsuhiro
    Zheng, Wei
    Zhu, Dingliang
    Vineis, Paolo
    Kyrtopoulos, Soterios A.
    Kleinjans, Jos C. S.
    McCarthy, Mark I.
    Soong, Richie
    Gieger, Christian
    Scott, James
    Teo, Yik-Ying
    He, Jiang
    Elliott, Paul
    Tai, E. Shyong
    van der Harst, Pim
    Kooner, Jaspal S.
    Chambers, John C.
    Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 11, p. 1282-1293Article in journal (Refereed)
    Abstract [en]

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

  • 127. Kenna, Kevin P.
    et al.
    van Doormaal, Perry T. C.
    Dekker, Annelot M.
    Ticozzi, Nicola
    Kenna, Brendan J.
    Diekstra, Frank P.
    van Rheenen, Wouter
    van Eijk, Kristel R.
    Jones, Ashley R.
    Keaglel, Pamela
    Shatunov, Aleksey
    Sproviero, William
    Smiths, Bradley N.
    van Es, Michael A.
    Topps, Simon D.
    Kenna, Aoife
    Miller, Jack W.
    Fallini, Claudia
    Tiloca, Cinzia
    McLaughlin, Russell L.
    Vance, Caroline
    Troakes, Claire
    Colombrita, Claudia
    Mora, Gabriele
    Calvo, Andrea
    Verde, Federico
    Al-Sarraj, Safa
    King, Andrew
    Calini, Daniela
    de Belleroche, Jacqueline
    Baas, Frank
    van der Kooi, Anneke J.
    de Visser, Marianne
    ten Asbroek, Anneloor L. M. A.
    Sapp, Peter C.
    McKenna-Yasek, Diane
    Polak, Meraida
    Asress, Seneshaw
    Luis Munoz-Blanco, Jose
    Strom, Tim M.
    Meitinger, Thomas
    Morrison, Karen E.
    Lauria, Giuseppe
    Williams, Kelly L.
    Leigh, P. Nigel
    Nicholson, Garth A.
    Blair, Ian P.
    Leblond, Claire S.
    Dion, Patrick A.
    Rouleau, Guy A.
    Pall, Hardev
    Shaw, Pamela J.
    Turner, Martin R.
    Talbot, Kevin
    Taroni, Franco
    Boylan, Kevin B.
    Van Blitterswijk, Marka
    Rademakers, Rosa
    Esteban-Perez, Jesus
    Garcia-Redondo, Alberto
    Van Damme, Phillip
    Robberecht, Wim
    Chio, Adrian
    Gellera, Cinzia
    Drepper, Carsten
    Sendtner, Michael
    Ratti, Antonia
    Glass, Jonathan D.
    Mora, Jesus S.
    Basak, Nazli A.
    Hardiman, Orla
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Weishaupt, Jochen H.
    Brown, Robert H., Jr.
    Al-Chalabi, Ammar
    Silani, Vincenzo
    Shaw, Christopher E.
    van den Berg, Leonard H.
    Veldink, Jan H.
    Landers, John E.
    D'Alfonso, Sandra
    Mazzini, Letizia
    Comi, Giacomo P.
    Del Bo, Roberto
    Ceroni, Mauro
    Gagliardi, Stella
    Querin, Giorgia
    Bertolin, Cinzia
    Pensato, Viviana
    Castellotti, Barbara
    Corti, Stefania
    Cereda, Cristina
    Corrado, Lucia
    Soraru, Gianni
    NEK1 variants confer susceptibility to amyotrophic lateral sclerosis2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 9, p. 1037-1042Article in journal (Refereed)
    Abstract [en]

    To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

  • 128. Kilpelainen, Tuomas O.
    et al.
    Bentley, Amy R.
    Noordam, Raymond
    Sung, Yun Ju
    Schwander, Karen
    Winkler, Thomas W.
    Jakupovic, Hermina
    Chasman, Daniel I.
    Manning, Alisa
    Ntalla, Ioanna
    Aschard, Hugues
    Brown, Michael R.
    de las Fuentes, Lisa
    Franceschini, Nora
    Guo, Xiuqing
    Vojinovic, Dina
    Aslibekyan, Stella
    Feitosa, Mary F.
    Kho, Minjung
    Musani, Solomon K.
    Richard, Melissa
    Wang, Heming
    Wang, Zhe
    Bartz, Traci M.
    Bielak, Lawrence F.
    Campbell, Archie
    Dorajoo, Rajkumar
    Fisher, Virginia
    Hartwig, Fernando P.
    Horimoto, Andrea R. V. R.
    Li, Changwei
    Lohman, Kurt K.
    Marten, Jonathan
    Sim, Xueling
    Smith, Albert V.
    Tajuddin, Salman M.
    Alver, Maris
    Amini, Marzyeh
    Boissel, Mathilde
    Chai, Jin Fang
    Chen, Xu
    Divers, Jasmin
    Evangelou, Evangelos
    Gao, Chuan
    Graff, Mariaelisa
    Harris, Sarah E.
    He, Meian
    Hsu, Fang-Chi
    Jackson, Anne U.
    Zhao, Jing Hua
    Kraja, Aldi T.
    Kuehnel, Brigitte
    Laguzzi, Federica
    Lyytikainen, Leo-Pekka
    Nolte, Ilja M.
    Rauramaa, Rainer
    Riaz, Muhammad
    Robino, Antonietta
    Rueedi, Rico
    Stringham, Heather M.
    Takeuchi, Fumihiko
    van der Most, Peter J.
    Varga, Tibor V.
    Verweij, Niek
    Ware, Erin B.
    Wen, Wanqing
    Li, Xiaoyin
    Yanek, Lisa R.
    Amin, Najaf
    Arnett, Donna K.
    Boerwinkle, Eric
    Brumat, Marco
    Cade, Brian
    Canouil, Mickael
    Chen, Yii-Der Ida
    Concas, Maria Pina
    Connell, John
    de Mutsert, Renee
    de Silva, H. Janaka
    de Vries, Paul S.
    Demirkan, Ayse
    Ding, Jingzhong
    Eaton, Charles B.
    Faul, Jessica D.
    Friedlander, Yechiel
    Gabriel, Kelley P.
    Ghanbari, Mohsen
    Giulianini, Franco
    Gu, Chi Charles
    Gu, Dongfeng
    Harris, Tamara B.
    He, Jiang
    Heikkinen, Sami
    Heng, Chew-Kiat
    Hunt, Steven C.
    Ikram, M. Arfan
    Jonas, Jost B.
    Koh, Woon-Puay
    Komulainen, Pirjo
    Krieger, Jose E.
    Kritchevsky, Stephen B.
    Kutalik, Zoltan
    Kuusisto, Johanna
    Langefeld, Carl D.
    Langenberg, Claudia
    Launer, Lenore J.
    Leander, Karin
    Lemaitre, Rozenn N.
    Lewis, Cora E.
    Liang, Jingjing
    Alizadeh, Behrooz Z.
    Boezen, H. Marike
    Franke, Lude
    Navis, Gerjan
    Rots, Marianne
    Swertz, Morris
    Wolffenbuttel, Bruce H. R.
    Wijmenga, Cisca
    Liu, Jianjun
    Magi, Reedik
    Manichaikul, Ani
    Meitinger, Thomas
    Metspalu, Andres
    Milaneschi, Yuri
    Mohlke, Karen L.
    Mosley, Thomas H., Jr.
    Murray, Alison D.
    Nalls, Mike A.
    Nang, Ei-Ei Khaing
    Nelson, Christopher P.
    Nona, Sotoodehnia
    Norris, Jill M.
    Nwuba, Chiamaka Vivian
    O'Connell, Jeff
    Palmer, Nicholette D.
    Papanicolau, George J.
    Pazoki, Raha
    Pedersen, Nancy L.
    Peters, Annette
    Peyser, Patricia A.
    Polasek, Ozren
    Porteous, David J.
    Poveda, Alaitz
    Raitakari, Olli T.
    Rich, Stephen S.
    Risch, Neil
    Robinson, Jennifer G.
    Rose, Lynda M.
    Rudan, Igor
    Schreiner, Pamela J.
    Scott, Robert A.
    Sidney, Stephen S.
    Sims, Mario
    Smith, Jennifer A.
    Snieder, Harold
    Sofer, Tamar
    Starr, John M.
    Sternfeld, Barbara
    Strauch, Konstantin
    Tang, Hua
    Taylor, Kent D.
    Tsai, Michael Y.
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    van der Ende, M. Yldau
    van Heemst, Diana
    Voortman, Trudy
    Waldenberger, Melanie
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wilson, Gregory
    Xiang, Yong-Bing
    Yao, Jie
    Yu, Caizheng
    Yuan, Jian-Min
    Zhao, Wei
    Zonderman, Alan B.
    Becker, Diane M.
    Boehnke, Michael
    Bowden, Donald W.
    de Faire, Ulf
    Deary, Ian J.
    Elliott, Paul
    Esko, Tonu
    Freedman, Barry I.
    Froguel, Philippe
    Gasparini, Paolo
    Gieger, Christian
    Kato, Norihiro
    Laakso, Markku
    Lakka, Timo A.
    Lehtimaaki, Terho
    Magnusson, Patrik K. E.
    Oldehinkel, Albertine J.
    Penninx, Brenda W. J. H.
    Samani, Nilesh J.
    Shu, Xiao-Ou
    van der Harst, Pim
    Van Vliet-Ostaptchouk, Jana V.
    Vollenweider, Peter
    Wagenknecht, Lynne E.
    Wang, Ya X.
    Wareham, Nicholas J.
    Weir, David R.
    Wu, Tangchun
    Zheng, Wei
    Zhu, Xiaofeng
    Evans, Michele K.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Harvard T. H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, USA; OCDEM, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
    Gudnason, Vilmundur
    Hayward, Caroline
    Horta, Bernardo L.
    Kelly, Tanika N.
    Liu, Yongmei
    North, Kari E.
    Pereira, Alexandre C.
    Ridker, Paul M.
    Tai, E. Shyong
    van Dam, Rob M.
    Fox, Ervin R.
    Kardia, Sharon L. R.
    Liu, Ching-Ti
    Mook-Kanamori, Dennis O.
    Province, Michael A.
    Redline, Susan
    van Duijn, Cornelia M.
    Rotter, Jerome I.
    Kooperberg, Charles B.
    Gauderman, W. James
    Psaty, Bruce M.
    Rice, Kenneth
    Munroe, Patricia B.
    Fornage, Myriam
    Cupples, L. Adrienne
    Rotimi, Charles N.
    Morrison, Alanna C.
    Rao, Dabeeru C.
    Loos, Ruth J. F.
    Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 376Article in journal (Refereed)
    Abstract [en]

    Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol- increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

  • 129. Kim, Sunhong
    et al.
    Johnson, Wade
    Chen, Changchun
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sewell, Aileen K
    Byström, Anders S
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Han, Min
    Allele-specific suppressors of lin-1(R175Opal) identify functions of MOC-3 and DPH-3 in tRNA modification complexes in Caenorhabditis elegans2010In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 185, no 4, p. 1235-1247Article in journal (Refereed)
    Abstract [en]

    The elongator (ELP) complex consisting of Elp1-6p has been indicated to play roles in multiple cellular processes. In yeast, the ELP complex has been shown to genetically interact with Uba4p/Urm1p and Kti11-13p for a function in tRNA modification. Through a Caenorhabditis elegans genetic suppressor screen and positional cloning, we discovered that loss-of-function mutations of moc-3 and dph-3, orthologs of the yeast UBA4 and KTI11, respectively, effectively suppress the Multivulva (Muv) phenotype of the lin-1(e1275, R175Opal) mutation. These mutations do not suppress the Muv phenotype caused by other lin-1 alleles or by gain-of-function alleles of ras or raf that act upstream of lin-1. The suppression can also be reverted by RNA interference of lin-1. Furthermore, we showed that dph-3(lf) also suppressed the defect of lin-1(e1275) in promoting the expression of a downstream target (egl-17). These results indicate that suppression by the moc-3 and dph-3 mutations is due to the elevated activity of lin-1(e1275) itself rather than the altered activity of a factor downstream of lin-1. We further showed that loss-of-function mutations of urm-1 and elpc-1-4, the worm counterparts of URM1 and ELP complex components in yeast, also suppressed lin-1(e1275). We also confirmed that moc-3(lf) and dph-3(lf) have defects in tRNA modifications as do the mutants of their yeast orthologs. These results, together with the observation of a likely readthrough product from a lin-1(e1275)∷gfp fusion transgene indicate that the aberrant tRNA modification led to failed recognition of a premature stop codon in lin-1(e1275). Our genetic data suggest that the functional interaction of moc-3/urm-1 and dph-3 with the ELP complex is an evolutionarily conserved mechanism involved in tRNA functions that are important for accurate translation.

  • 130. Kostjukovits, Svetlana
    et al.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pekkinen, Minna
    Klemetti, Paula
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Taskinen, Mervi
    Makitie, Outi
    Decreased telomere length in children with cartilage-hair hypoplasia2017In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 54, no 5, p. 365-370Article in journal (Refereed)
    Abstract [en]

    Background Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features. Methods The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2 years, range 6.0-70.8 years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR. Results Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=-0.482, p < 0.001) and non-carriers (r=-0.498, p<0.001), but not in patients (r=-0.236, p=0.107). In particular children (< 18 years) with CHH had shorter telomeres than controls (median RTL 1.12 vs 1.26, p=0.008). In patients with CHH, RTL showed no correlation with genotype, clinical or laboratory characteristics. Conclusions Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.

  • 131. Krauskopf, Julian
    et al.
    de Kok, Theo M
    Hebels, Dennie G
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Spaeth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kiviranta, Hannu
    Rantakokko, Panu
    Kyrtopoulos, Soterios A
    Kleinjans, Jos C
    MicroRNA profile for health risk assessment: environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 9262Article in journal (Refereed)
    Abstract [en]

    Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker-based environmental health risk assessment.

  • 132. Kurbasic, Azra
    et al.
    Poveda, Alaitz
    Chen, Yan
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Engberg, Elisabeth
    Umeå University, Faculty of Social Sciences, Demographic Data Base.
    Hu, Frank B
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Barroso, Ines
    Brändström, Anders
    Umeå University, Faculty of Social Sciences, Demographic Data Base.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Gene-Lifestyle Interactions in Complex Diseases: Design and Description of the GLACIER and VIKING Studies2014In: Current nutrition reports, ISSN 2161-3311, Vol. 3, no 4, p. 400-411Article in journal (Refereed)
    Abstract [en]

    Most complex diseases have well-established genetic and non-genetic risk factors. In some instances, these risk factors are likely to interact, whereby their joint effects convey a level of risk that is either significantly more or less than the sum of these risks. Characterizing these gene-environment interactions may help elucidate the biology of complex diseases, as well as to guide strategies for their targeted prevention. In most cases, the detection of gene-environment interactions will require sample sizes in excess of those needed to detect the marginal effects of the genetic and environmental risk factors. Although many consortia have been formed, comprising multiple diverse cohorts to detect gene-environment interactions, few robust examples of such interactions have been discovered. This may be because combining data across studies, usually through meta-analysis of summary data from the contributing cohorts, is often a statistically inefficient approach for the detection of gene-environment interactions. Ideally, single, very large and well-genotyped prospective cohorts, with validated measures of environmental risk factor and disease outcomes should be used to study interactions. The presence of strong founder effects within those cohorts might further strengthen the capacity to detect novel genetic effects and gene-environment interactions. Access to accurate genealogical data would also aid in studying the diploid nature of the human genome, such as genomic imprinting (parent-of-origin effects). Here we describe two studies from northern Sweden (the GLACIER and VIKING studies) that fulfill these characteristics.

  • 133. Kvarnung, Malin
    et al.
    Taylan, Fulya
    Nilsson, Daniel
    Anderlid, Britt-Marie
    Malmgren, Helena
    Lagerstedt-Robinson, Kristina
    Holmberg, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Burstedt, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nordenskjöld, Magnus
    Nordgren, Ann
    Lundberg, Elisabeth S.
    Genomic screening in rare disorders: new mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability2018In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 94, no 6, p. 528-537Article in journal (Refereed)
    Abstract [en]

    We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants. We highlight the findings in two affected siblings with splice altering variants in ALG14 and propose a new clinical entity, which includes severe intellectual disability, epilepsy, behavioral problems and mild dysmorphic features, caused by biallelic variants in ALG14.

  • 134.
    Köhn, Linda
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Genetic mapping of retinal degenerations in Northern Sweden2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Inherited retinal degenerations are a group of disorders characterised by great genetic heterogeneity. Clinically, they can be divided into two large groups of diseases, those associated with night blindness, e.g. retinitis pigmentosa (RP), and those with macular malfunction, e.g. cone/cone-rod dystrophy (COD/CORD). This thesis is focused on finding the genetic basis of disease in families with autosomal dominant COD, autosomal dominant RP, and Bothnia dystrophy (BD), a regional variant of RP. 

     A variant of COD was previously mapped to 17p12-p13 in a family from northern Sweden. One additional family originating from the same geographical area was included in fine mapping of this chromosome region. Using 12 microsatellite markers in linkage and haplotype analysis, the region was refined from 26.9 to 14.3 cM. A missense mutation, Q626H, in an evolutionarily conserved region of PITPNM3, phosphatidylinositol transfer membrane-associated protein, was identified. The mutation segregated with the disease in both families and was absent from normal control chromosomes. PITPNM3 is a human homologue of the Drosophila retinal degeneration (rdgB) protein, which is highly expressed in the retina and has been proposed to be required for membrane turnover of photoreceptor cells.

    With the intention of establishing the global impact that PITPNM3 has on retinal degenerations 165 DNA samples from COD and CORD patients were obtained from Denmark, Germany, the UK, and USA and screened for mutations. The Q626H mutation found in the Swedish families was also found in one British family and a novel Q342P variant was detected in a German patient. In addition, two intronic variants were identified: c.900+60C>T and c.901-45G>A. Thus, we concluded that mutations in PITPNM3 represent a rare cause of COD worldwide.

    In two large families from northern Sweden showing autosomal dominant RP with reduced penetrance, the disease locus was mapped using genome-wide linkage analysis to 19q13.42 (RP11). Since mutation screening of eight genes on 19q13.42 revealed no mutations, multiplex ligation-dependent probe amplification (MLPA) was used to screen for large genomic abnormalities in PRPF31, RHO, RP1, RPE65, and IMPDH1. A large deletion spanning 11 exons of PRPF31 and three genes upstream was identified. Using long-range PCR, the breakpoints of the deletion were identified and the size of the deletion was determined to encompass almost 59 kb.

    BD is an autosomal recessive type of RP with high prevalence in northern Sweden. The disease is associated with a c.700C>T mutation in RLBP1. In a screening of recessive RP in northern Sweden, 67 patients were found to be homozygous for c.700C>T and 10 patients were heterozygous. An evaluation with arrayed primer extension (APEX) technology revealed a second mutation, c.677T>A, in RLBP1 giving rise to compound heterozygosity in these patients. In addition, a c.40C>T exchange in CAIV was detected in a patient with BD and in 143 healthy blood donors. The c.40C>T substitution in CAIV has been reported to cause autosomal dominant RP in South African families with European ancestry. However, in the population of northern Sweden it appears to be a benign polymorphism.

    In summary, a first mutation in PITPNM3, encoding a human homologue of the Drosophila retinal degeneration protein, was detected in two large families with COD. A large deletion in PRPF31 was discovered in two families with autosomal dominant RP showing reduced penetrance and in 10 patients BD was shown to be caused by two allelic mutations in RLBP1.

  • 135.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bowne, Sara J
    The University of Texas Health Science Center, Laboratory for Molecular Diagnosis of Inherited Eye Diseases, Human Genetics Center .
    Daiger, Stephen P
    The University of Texas Health Science Center, Laboratory for Molecular Diagnosis of Inherited Eye Diseases, Human Genetics Center .
    Burstedt, Marie SI
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Kadzhaev, Konstantin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Breakpoint characterization of a novel ~59 kb genomic deletion on 19q13.42 in autosomal dominant retinitis pigmentosa with reduced penetrance2009In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, no 5, p. 651-655Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.

  • 136.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Burstedt, Marie SI
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Jonsson, Frida
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Kadzhaev, Konstantin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Haamer, Eneli
    Asper Biotech, Tartu, Estonia.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP12008In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 49, no 7, p. 3172-3177Article in journal (Refereed)
    Abstract [en]

    Purpose: Bothnia dystrophy (BD) is an autosomal recessive retinitis pigmentosa (arRP) associated with the c.700C>T mutation in the RLBP1 gene. Testing of patients with BD has revealed the c.700C>T mutation on one or both alleles. The purpose of this study was to elucidate the underlying genetic mechanisms along with a clinical evaluation of the heterozygous patients with BD.

    Methods: Patients with BD heterozygous for the RLBP1 c.700C>T were tested for 848 mutations by arrayed primer-extension technology. Further mutation detection was performed by PCR-restriction fragment length polymorphism (RFLP), sequencing, denaturing (d)HLPC and allelic discrimination. The ophthalmic examinations were performed in all c.700C>T heterozygotes.

    Results: The clinical findings in 10 BD heterozygotes were similar to those in the homozygotes. The presence of a second mutation, c.677T>A, corresponding to p.M226K was detected in all 10 cases. Segregation analysis showed that the mutations were allelic, and the patients were compound heterozygotes [c.677T>A]+[c.700C>T]. One of those patients was also a carrier of the c.40C>T corresponding to the p.R14W change in carbonic anhydrase IV (CAIV) associated with autosomal dominant RP, RP17. His mother, a carrier of the identical change was declared healthy after ophthalmic examination. This sequence variant was found in 6 of 143 tested blood donors.

    Conclusions: The high frequency of arRP in northern Sweden is due to two mutations in the RLBP1 gene: c.677T>A and c.700C>T. BD is caused by the loss of CRALBP function due to changed physical features and impaired activity of retinoid binding. The CAIV p.R14W sequence variant found in one of the patients with a BD phenotype is a benign polymorphism in a population of northern Sweden.

  • 137.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Kadzhaev, Konstantin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Burstedt, Marie SI
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 6, p. 664-671Article in journal (Refereed)
    Abstract [en]

    Autosomal dominant cone dystrophy (CORD5) (MIM 600977) is a rare disease predominantly affecting cone photoreceptors. Here we refine the CORD5 locus previously mapped to 17p13 from 27 to 14.3 cM and identified a missense mutation, Q626H in the phosphatidylinositol transfer (PIT) membrane-associated protein (PITPNM3) (MIM 608921) in two Swedish families. PITPNM3, known as a human homologue of the Drosophila retinal degeneration B (rdgB), lacks the N-terminal PIT domain needed for transport of phospholipids, renewal of photoreceptors membrane and providing the electroretinogram (ERG) response to light. In our study, the mutation causing CORD5 is located in the C-terminal region interacting with a member of nonreceptor protein tyrosine kinases, PYK2. Our finding on the first mutation in the human homologue of Drosophila rdgB indicates novel pathways and a potential important role of the PITPNM3 in mammalian phototransduction.

  • 138.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Kohl, Susanne
    Bowne, Sara J
    Sullivan, Lori S
    Kellner, Ulrich
    Daiger, Stephen P
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    PITPNM3 is an uncommon cause of cone and cone-rod dystrophies.2010In: Ophthalmic Genetics, ISSN 1381-6810, E-ISSN 1744-5094, Vol. 31, no 3, p. 139-140Article in journal (Refereed)
    Abstract [en]

    The first mutation in PITPNM3, a human homologue of the Drosophila retinal degeneration (rdgB not not) gene was reported in two large Swedish families with autosomal dominant cone dystrophy. To establish the global impact that PITPNM3 has on retinal degenerations we screened 163 patients from Denmark, Germany, the UK, and USA. Four sequence variants, two missence mutations and two intronic changes were identified in the screen. Thus, mutations in PITPNM3 do not appear to be a major cause of cone or cone-rod dystrophy.

  • 139. Laitman, Yael
    et al.
    Feng, Bing-Jian
    Zamir, Itay M
    The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
    Weitzel, Jeffrey N
    Duncan, Paul
    Port, Danielle
    Thirthagiri, Eswary
    Teo, Soo-Hwang
    Evans, Gareth
    Latif, Ayse
    Newman, William G
    Gershoni-Baruch, Ruth
    Zidan, Jamal
    Shimon-Paluch, Shani
    Goldgar, David
    Friedman, Eitan
    Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 2, p. 212-216Article in journal (Refereed)
    Abstract [en]

    The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ~5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~650 years ago, and into the Iraqi-Jewish community ~450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.

  • 140. Langefeld, Carl D.
    et al.
    Ainsworth, Hannah C.
    Graham, Deborah S. Cunninghame
    Kelly, Jennifer A.
    Comeau, Mary E.
    Marion, Miranda C.
    Howard, Timothy D.
    Ramos, Paula S.
    Croker, Jennifer A.
    Morris, David L.
    Sandling, Johanna K.
    Almlof, Jonas Carlsson
    Acevedo-Vasquez, Eduardo M.
    Alarcon, Graciela S.
    Babini, Alejandra M.
    Baca, Vicente
    Bengtsson, Anders A.
    Berbotto, Guillermo A.
    Bijl, Marc
    Brown, Elizabeth E.
    Brunner, Hermine I.
    Cardiel, Mario H.
    Catoggio, Luis
    Cervera, Ricard
    Cucho-Venegas, Jorge M.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    D'Alfonso, Sandra
    Da Silva, Berta Martins
    de la Rua Figueroa, Inigo
    Doria, Andrea
    Edberg, Jeffrey C.
    Endreffy, Emoke
    Esquivel-Valerio, Jorge A.
    Fortin, Paul R.
    Freedman, Barry I.
    Frostegard, Johan
    Garcia, Mercedes A.
    Garcia de la Torre, Ignacio
    Gilkeson, Gary S.
    Gladman, Dafna D.
    Gunnarsson, Iva
    Guthridge, Joel M.
    Huggins, Jennifer L.
    James, Judith A.
    Kallenberg, Cees G. M.
    Kamen, Diane L.
    Karp, David R.
    Kaufman, Kenneth M.
    Kottyan, Leah C.
    Kovacs, Laszlo
    Laustrup, Helle
    Lauwerys, Bernard R.
    Li, Quan-Zhen
    Maradiaga-Cecena, Marco A.
    Martin, Javier
    McCune, Joseph M.
    McWilliams, David R.
    Merrill, Joan T.
    Miranda, Pedro
    Moctezuma, Jose F.
    Nath, Swapan K.
    Niewold, Timothy B.
    Orozco, Lorena
    Ortego-Centeno, Norberto
    Petri, Michelle
    Pineau, Christian A.
    Pons-Estel, Bernardo A.
    Pope, Janet
    Raj, Prithvi
    Ramsey-Goldman, Rosalind
    Reveille, John D.
    Russell, Laurie P.
    Sabio, Jose M.
    Aguilar-Salinas, Carlos A.
    Scherbarth, Hugo R.
    Scorza, Raffaella
    Seldin, Michael F.
    Sjowall, Christopher
    Svenungsson, Elisabet
    Thompson, Susan D.
    Toloza, Sergio M. A.
    Truedsson, Lennart
    Tusie-Luna, Teresa
    Vasconcelos, Carlos
    Vila, Luis M.
    Wallace, Daniel J.
    Weisman, Michael H.
    Wither, Joan E.
    Bhangale, Tushar
    Oksenberg, Jorge R.
    Rioux, John D.
    Gregersen, Peter K.
    Syvanen, Ann-Christine
    Ronnblom, Lars
    Criswell, Lindsey A.
    Jacob, Chaim O.
    Sivils, Kathy L.
    Tsao, Betty P.
    Schanberg, Laura E.
    Behrens, Timothy W.
    Silverman, Earl D.
    Alarcon-Riquelme, Marta E.
    Kimberly, Robert P.
    Harley, John B.
    Wakeland, Edward K.
    Graham, Robert R.
    Gaffney, Patrick M.
    Vyse, Timothy J.
    Transancestral mapping and genetic load in systemic lupus erythematosus2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 16021Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

  • 141. Lappalainen, T
    et al.
    Laitinen, V
    Salmela, E
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Huoponen, K
    Savontaus, M-L
    Lahermo, P
    Migration waves to the Baltic Sea region2008In: Annals of Human Genetics, ISSN 0003-4800, E-ISSN 1469-1809, Vol. 72, p. 337-348Article in journal (Refereed)
    Abstract [en]

    In this study, the population history of the Baltic Sea region, known to be affected by a variety of migrations and genetic barriers, was analyzed using both mitochondrial DNA and Y-chromosomal data. Over 1200 samples from Finland, Sweden, Karelia, Estonia, Setoland, Latvia and Lithuania were genotyped for 18 Y-chromosomal biallelic polymorphisms and 9 STRs, in addition to analyzing 17 coding region polymorphisms and the HVS1 region from the mtDNA. It was shown that the populations surrounding the Baltic Sea are genetically similar, which suggests that it has been an important route not only for cultural transmission but also for population migration. However, many of the migrations affecting the area from Central Europe, the Volga-Ural region and from Slavic populations have had a quantitatively different impact on the populations, and, furthermore, the effects of genetic drift have increased the differences between populations especially in the north. The possible explanations for the high frequencies of several haplogroups with an origin in the Iberian refugia (H1, U5b, I1a) are also discussed.

  • 142. Laskar, Ruhina S
    et al.
    Muller, David C
    Li, Peng
    Machiela, Mitchell J
    Ye, Yuanqing
    Gaborieau, Valerie
    Foll, Matthieu
    Hofmann, Jonathan N
    Colli, Leandro
    Sampson, Joshua N
    Wang, Zhaoming
    Bacq-Daian, Delphine
    Boland, Anne
    Abedi-Ardekani, Behnoush
    Durand, Geoffroy
    Le Calvez-Kelm, Florence
    Robinot, Nivonirina
    Blanche, Helene
    Prokhortchouk, Egor
    Skryabin, Konstantin G
    Burdett, Laurie
    Yeager, Meredith
    Radojevic-Skodric, Sanja
    Savic, Slavisa
    Foretova, Lenka
    Holcatova, Ivana
    Janout, Vladimir
    Mates, Dana
    Rascu, Stefan
    Mukeria, Anush
    Zaridze, David
    Bencko, Vladimir
    Cybulski, Cezary
    Fabianova, Eleonora
    Jinga, Viorel
    Lissowska, Jolanta
    Lubinski, Jan
    Navratilova, Marie
    Rudnai, Peter
    Świątkowska, Beata
    Benhamou, Simone
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Trichopoulou, Antonia
    Riboli, Elio
    Overvad, Kim
    Panico, Salvatore
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Giles, Graham G
    Milne, Roger L
    Severi, Gianluca
    Bruinsma, Fiona
    Fletcher, Tony
    Koppova, Kvetoslava
    Larsson, Susanna C
    Wolk, Alicja
    Banks, Rosamonde E
    Selby, Peter J
    Easton, Douglas F
    Pharoah, Paul
    Andreotti, Gabriella
    Beane Freeman, Laura E
    Koutros, Stella
    Albanes, Demetrius
    Männistö, Satu
    Weinstein, Stephanie
    Clark, Peter E
    Edwards, Todd L
    Lipworth, Loren
    Carol, Hallie
    Freedman, Matthew L
    Pomerantz, Mark M
    Cho, Eunyoung
    Kraft, Peter
    Preston, Mark A
    Wilson, Kathryn M
    Michael Gaziano, J
    Sesso, Howard D
    Black, Amanda
    Freedman, Neal D
    Huang, Wen-Yi
    Anema, John G
    Kahnoski, Richard J
    Lane, Brian R
    Noyes, Sabrina L
    Petillo, David
    Teh, Bin Tean
    Peters, Ulrike
    White, Emily
    Anderson, Garnet L
    Johnson, Lisa
    Luo, Juhua
    Chow, Wong-Ho
    Moore, Lee E
    Choueiri, Toni K
    Wood, Christopher
    Johansson, Mattias
    McKay, James D
    Brown, Kevin M
    Rothman, Nathaniel
    Lathrop, Mark G
    Deleuze, Jean-Francois
    Wu, Xifeng
    Brennan, Paul
    Chanock, Stephen J
    Purdue, Mark P
    Scelo, Ghislaine
    Sex specific associations in genome wide association analysis of renal cell carcinoma2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

  • 143. Lee, Hun-Goo
    et al.
    Kahn, Tatyana G.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Rutgers State Univ, Mol Biol & Biochem, Piscataway, NJ 08854 USA.
    Simcox, Amanda
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Rutgers State Univ, Mol Biol & Biochem, Piscataway, NJ 08854 USA.
    Pirrotta, Vincenzo
    Genome-wide activities of Polycomb complexes control pervasive transcription2015In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 25, no 8, p. 1170-1181Article in journal (Refereed)
    Abstract [en]

    Polycomb group (PcG) complexes PRC1 and PRC2 are well known for silencing specific developmental genes. PRC2 is a methyltransferase targeting histone H3K27 and producing H3K27me3, essential for stable silencing. Less well known but quantitatively much more important is the genome-wide role of PRC2 that dimethylates similar to 70% of total H3K27. We show that H3K27me2 occurs in inverse proportion to transcriptional activity in most non-PcG target genes and intergenic regions and is governed by opposing roaming activities of PRC2 and complexes containing the H3K27 demethylase UTX. Surprisingly, loss of H3K27me2 results in global transcriptional derepression proportionally greatest in silent or weakly transcribed intergenic and genic regions and accompanied by an increase of H3K27ac and H3K4me1. H3K27me2 therefore sets a threshold that prevents random, unscheduled transcription all over the genome and even limits the activity of highly transcribed genes. PRC1-type complexes also have global roles. Unexpectedly, we find a pervasive distribution of histone H2A ubiquitylated at lysine 118 (H2AK118ub) outside of canonical PcG target regions, dependent on the RING/Sce subunit of PRC1-type complexes. We show, however, that H2AK118ub does not mediate the global PRC2 activity or the global repression and is predominantly produced by a new complex involving L(3) 73Ah, a homolog of mammalian PCGF3.

  • 144.
    Li, Chunyan
    et al.
    1Faculty of Public Health, Medical College of Xi’an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry of Education, Key Laboratory of Trace elements and Endemic Diseases of Ministry of Health, Xi’an, China; Institute of Health Education of Xi’an, Xi’an, China.
    Wang, Weizhuo
    Department of Orthopedics Surgery, Second Hospital, Xi’an Jiaotong University, Xi’an, China.
    Guo, Xiong
    Faculty of Public Health, Medical College of Xi’an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry of Education, Key Laboratory of Trace elements and Endemic Diseases of Ministry of Health, Xi’an, China.
    Zhang, Feng
    Faculty of Public Health, Medical College of Xi’an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry of Education, Key Laboratory of Trace elements and Endemic Diseases of Ministry of Health, Xi’an, China.
    Ma, Weijuan
    Faculty of Public Health, Medical College of Xi’an Jiaotong University, Key Laboratory of Environment and Gene Related Diseases of Ministry of Education, Key Laboratory of Trace elements and Endemic Diseases of Ministry of Health, Xi’an, China.
    Zhang, Yingang
    Department of Orthopedics Surgery, First Hospital, Xi’an Jiaotong University, Xi’an, China.
    Li, Youfen
    School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China.
    Bai, Yidong
    Department of Cellular and Structural Biology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA.
    Lammi, Mikko
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Pathways related to mitochondrial dysfunction in cartilage of endemic osteoarthritis patients in China2012In: Science China Life Sciences, ISSN 1674-7305, Vol. 55, no 12, p. 1057-1063, article id 23233220Article in journal (Refereed)
    Abstract [en]

    n this paper, we present the first evidence of differences in the mitochondria-related gene expression profiles of adult articular cartilage derived from patients with Kashin-Beck disease and normal controls. The expression of 705 mitochondria-related genes was analyzed by mitochondria-related gene expression analysis and ingenuity pathways analysis. Mitochondria-related gene expression analysis identified 9 up-regulated genes in Kashin-Beck disease based on their average expression ratio. Three canonical pathways involved in oxidative phosphorylation, apoptosis signaling and pyruvate metabolism were identified, which indicate the involvement of mitochondrial dysfunction in the pathogenesis of Kashin-Beck disease.

  • 145. Li, Sherly X.
    et al.
    Imamura, Fumiaki
    Ye, Zheng
    Schulze, Matthias B.
    Zheng, Jusheng
    Ardanaz, Eva
    Arriola, Larraitz
    Boeing, Heiner
    Dow, Courtney
    Fagherazzi, Guy
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lund Univ, Sweden.
    Agudo, Antonio
    Grioni, Sara
    Kaaks, Rudolf
    Katzke, Verena A.
    Key, Timothy J.
    Khaw, Kay Tee
    Mancini, Francesca R.
    Navarro, Carmen
    Nilsson, Peter M.
    Onland-Moret, N. Charlotte
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, J. Ramon
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tumino, Rosario
    Sharp, Stephen J.
    Riboli, Elio
    Langenberg, Claudia
    Scott, Robert A.
    Forouhi, Nita G.
    Wareham, Nicholas J.
    Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct2017In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 106, no 1, p. 263-275Article, review/survey (Refereed)
    Abstract [en]

    Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. Objective: We aimed to identify existing evidence for genemacronutrient interactions and T2D and to examine the reported interactions in a large-scale study. Design: We systematically reviewed studies reporting genemacronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e. g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate countryspecific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Results: Thirteen observational studies met the eligibility criteria (n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (v-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction, 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.

  • 146. Lin, Chia-Yeh
    et al.
    Wu, Meng-Ying
    Gay, Sophie
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lai, Mong Sing
    Hsiao, Wei-Chun
    Hung, Shih-Hsun
    Tseng, Hsin-Yi
    Wright, Duncan Edward
    Wang, Chen-Yi
    Hsu, Guoo-Shyng W
    Devys, Didier
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kao, Cheng-Fu
    H2B Mono-ubiquitylation Facilitates Fork Stalling and Recovery during Replication Stress by Coordinating Rad53 Activation and Chromatin Assembly2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 10, p. e1004667-Article in journal (Refereed)
    Abstract [en]

    The influence of mono-ubiquitylation of histone H2B (H2Bub) on transcription via nucleosome reassembly has been widely documented. Recently, it has also been shown that H2Bub promotes recovery from replication stress; however, the underling molecular mechanism remains unclear. Here, we show that H2B ubiquitylation coordinates activation of the intra-S replication checkpoint and chromatin re-assembly, in order to limit fork progression and DNA damage in the presence of replication stress. In particular, we show that the absence of H2Bub affects replication dynamics (enhanced fork progression and reduced origin firing), leading to γH2A accumulation and increased hydroxyurea sensitivity. Further genetic analysis indicates a role for H2Bub in transducing Rad53 phosphorylation. Concomitantly, we found that a change in replication dynamics is not due to a change in dNTP level, but is mediated by reduced Rad53 activation and destabilization of the RecQ helicase Sgs1 at the fork. Furthermore, we demonstrate that H2Bub facilitates the dissociation of the histone chaperone Asf1 from Rad53, and nucleosome reassembly behind the fork is compromised in cells lacking H2Bub. Taken together, these results indicate that the regulation of H2B ubiquitylation is a key event in the maintenance of genome stability, through coordination of intra-S checkpoint activation, chromatin assembly and replication fork progression.

  • 147.
    Lind, Lisbet K
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Stecksén-Blicks, Christina
    Umeå University, Faculty of Medicine, Department of Odontology, Pediatric Dentistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    EDAR mutation in autosomal dominant hypohidrotic ectodermal dysplasia in two Swedish families2006In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 7, p. 80-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder characterized by defective development of teeth, hair, nails and eccrine sweat glands. Both autosomal dominant and autosomal recessive forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR) protein that plays an important role during embryogenesis.

    METHODS: The coding DNA sequence of the EDAR gene was analyzed in two large Swedish three-generational families with autosomal dominant HED.

    RESULTS: A non-sense C to T mutation in exon 12 was identified in both families. This disease-specific mutation changes an arginine amino acid in position 358 of the EDAR protein into a stop codon (p.Arg358X), thereby truncating the protein. In addition to the causative mutation two polymorphisms, not associated with the HED disorder, were also found in the EDAR gene.

    CONCLUSION: The finding of the p.Arg358X mutation in the Swedish families is the first corroboration of a previously described observation in an American family. Thus, our study strengthens the role of this particular mutation in the aetiology of autosomal dominant HED and confirms the importance of EDAR for the development of HED.

  • 148. Lindholm, Eva
    et al.
    Åberg, Karolina
    Ekholm, Birgit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Pettersson, Ulf
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Jazin, Elena E
    Reconstruction of ancestral haplotypes in a 12-generation schizophrenia pedigree2004In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 14, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    We searched for candidate chromosomal regions inherited identical by descent in 19 patients suffering from schizophrenia or schizoaffective disorder that are related 12 generations back, to an ancestral couple born in the middle of the seventeenth century. To accomplish this goal, we constructed complete chromosomal haplotypes for each patient using genotype data from 450 markers. In total, 12 haplotype regions (with sizes ranging from 0.6 to 10.9 cM) constituted by three markers each were identical in three or more of the affected individuals. The largest genomic segment was located on 6q25, a region previously shown to be significantly more frequent in patients than controls, and proposed to contain a schizophrenia susceptibility locus. For the remaining 11 candidate haplotypes, we estimated haplotype frequencies from all the 43 affected members collected from the same family and 46 unrelated control individuals. This analysis indicated that at least four of the 11 candidate haplotypes are ancestral, since the frequencies were significantly higher in patients than in controls. Five additional haplotypes showed higher estimated frequencies in the patients but the differences were not significant. Interestingly, five of these 11 genomic regions are located in, or close to, candidate regions previously suggested to contain susceptibility genes for schizophrenia. The regions are 5q21-23, 8p21-22, 1 0p13-15, 13q12-13 and 22q12-13. Several of these haplotypes are probably ancestral linkage disequilibrium blocks inherited from the original couple. There exists, however, the possibility that one or more of these regions harbour schizophrenia susceptibility loci that may have epistatic interactions among them.

  • 149. Lindqvist, Carl Marten
    et al.
    Nordlund, Jessica
    Ekman, Diana
    Johansson, Anna
    Moghadam, Behrooz Torabi
    Raine, Amanda
    Overnas, Elin
    Dahlberg, Johan
    Wahlberg, Per
    Henriksson, Niklas
    Abrahamsson, Jonas
    Frost, Britt-Marie
    Grander, Dan
    Heyman, Mats
    Larsson, Rolf
    Palle, Josefine
    Soderhall, Stefan
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Lonnerholm, Gudmar
    Syvanen, Ann-Christine
    Berglund, Eva C.
    The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 1, p. 118-128Article in journal (Refereed)
    Abstract [en]

    Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

  • 150. Lindstrand, Anna
    et al.
    Malmgren, Helena
    Verri, Annapia
    Benetti, Elisa
    Eriksson, Maud
    Nordgren, Ann
    Anderlid, Britt-Marie
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Schoumans, Jacqueline
    Blennow, Elisabeth
    Molecular and clinical characterization of patients with overlapping 10p deletions2010In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 152A, no 5, p. 1233-1243Article in journal (Refereed)
    Abstract [en]

    Chromosome 10p terminal deletions have been associated with DiGeorge phenotype, and within the same genomic region haploinsufficiency of GATA3 causes the HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia). We have performed detailed molecular analysis of four patients with partial overlapping 10p deletions by using FISH-mapping, array-CGH, and custom-designed high-resolution oligonucleotide array. All four patients had mental retardation and speech impairment and three of them showed variable signs of HDR syndrome. In addition, two patients had autistic behaviors and had similar dysmorphic features giving them a striking physical resemblance. A review of the literature identified 10 previously published cases with similar 10p deletions and reliable molecular or molecular cytogenetic mapping data. The combined information of present and previous cases suggests that partial deletions of 10p14-p15 represent a syndrome with a distinct and more severe phenotype than previously assumed. The main characteristics include severe mental retardation, language impairment, autistic behavior, and characteristic clinical features. A critical region involved in mental retardation and speech impairment is defined within 1.6 Mb in 10p15.3. In addition, deletion of 4.3 Mb within 10p14 is associated with autism and characteristic clinical findings.

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