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  • 1.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zheng, Wenjing
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gorre, Nagaraju
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hämäläinen, Tuula
    Cooney, Austin J
    Huhtaniemi, Ilpo
    Lan, Zi-Jian
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 3, p. 397-410Article in journal (Refereed)
    Abstract [en]

    To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.

  • 2.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zheng, Wenjing
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Shen, Yan
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Gorre, Nagaraju
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ning, Yao
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Halet, Guillaume
    Univ Rennes 1, CNRS, UMR 6061, Inst Genet & Dev Rennes, F-35043 Rennes, France .
    Kaldis, Philipp
    NUS, A STAR, IMCB, Singapore 138673, Singapore.
    Liu, Kui
    Univ Gothenburg, Dept Chem & Mol Biol, SE-40530 Gothenburg, Sweden.
    Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 11, p. 2476-2484Article in journal (Refereed)
    Abstract [en]

    Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Previous studies have shown that deletions of Cdk3, Cdk4 or Cdk6 in mice result in viable animals with normal oocyte maturation, indicating that these Cdks are not essential for the meiotic maturation of oocytes. In addition, conventional knockout of Cdk1 and Cdk2 leads to embryonic lethality and postnatal follicular depletion, respectively, making it impossible to study the functions of Cdk1 and Cdk2 in oocyte meiosis. In this study, we generated conditional knockout mice with oocyte-specific deletions of Cdk1 and Cdk2. We showed that the lack of Cdk1, but not of Cdk2, leads to female infertility due to a failure of the resumption of meiosis in the oocyte. Re-introduction of Cdk1 mRNA into Cdk1-null oocytes largely resumed meiosis. Thus, Cdk1 is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. We also found that Cdk1 maintains the phosphorylation status of protein phosphatase 1 and lamin A/C in oocytes in order for meiosis resumption to occur.

  • 3. Antoniou, Antonis C
    et al.
    Kartsonaki, Christiana
    Sinilnikova, Olga M
    Soucy, Penny
    McGuffog, Lesley
    Healey, Sue
    Lee, Andrew
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Cattaneo, Elisa
    Barile, Monica
    Pensotti, Valeria
    Pasini, Barbara
    Dolcetti, Riccardo
    Giannini, Giuseppe
    Putignano, Anna Laura
    Varesco, Liliana
    Radice, Paolo
    Mai, Phuong L
    Greene, Mark H
    Andrulis, Irene L
    Glendon, Gord
    Ozcelik, Hilmi
    Thomassen, Mads
    Gerdes, Anne-Marie
    Kruse, Torben A
    Birk Jensen, Uffe
    Crüger, Dorthe G
    Caligo, Maria A
    Laitman, Yael
    Milgrom, Roni
    Kaufman, Bella
    Paluch-Shimon, Shani
    Friedman, Eitan
    Loman, Niklas
    Harbst, Katja
    Lindblom, Annika
    Arver, Brita
    Ehrencrona, Hans
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nathanson, Katherine L
    Domchek, Susan M
    Rebbeck, Timothy
    Jakubowska, Ania
    Lubinski, Jan
    Gronwald, Jacek
    Huzarski, Tomasz
    Byrski, Tomasz
    Cybulski, Cezary
    Gorski, Bohdan
    Osorio, Ana
    Ramón y Cajal, Teresa
    Fostira, Florentia
    Andrés, Raquel
    Benitez, Javier
    Hamann, Ute
    Hogervorst, Frans B
    Rookus, Matti A
    Hooning, Maartje J
    Nelen, Marcel R
    van der Luijt, Rob B
    van Os, Theo A M
    van Asperen, Christi J
    Devilee, Peter
    Meijers-Heijboer, Hanne E J
    Garcia, Encarna B Gómez
    Peock, Susan
    Cook, Margaret
    Frost, Debra
    Platte, Radka
    Leyland, Jean
    Evans, D Gareth
    Lalloo, Fiona
    Eeles, Ros
    Izatt, Louise
    Adlard, Julian
    Davidson, Rosemarie
    Eccles, Diana
    Ong, Kai-ren
    Cook, Jackie
    Douglas, Fiona
    Paterson, Joan
    Kennedy, M John
    Miedzybrodzka, Zosia
    Godwin, Andrew
    Stoppa-Lyonnet, Dominique
    Buecher, Bruno
    Belotti, Muriel
    Tirapo, Carole
    Mazoyer, Sylvie
    Barjhoux, Laure
    Lasset, Christine
    Leroux, Dominique
    Faivre, Laurence
    Bronner, Myriam
    Prieur, Fabienne
    Nogues, Catherine
    Rouleau, Etienne
    Pujol, Pascal
    Coupier, Isabelle
    Frénay, Marc
    Hopper, John L
    Daly, Mary B
    Terry, Mary B
    John, Esther M
    Buys, Saundra S
    Yassin, Yosuf
    Miron, Alexander
    Goldgar, David
    Singer, Christian F
    Tea, Muy-Kheng
    Pfeiler, Georg
    Dressler, Anne Catharina
    Hansen, Thomas v O
    Jønson, Lars
    Ejlertsen, Bent
    Barkardottir, Rosa Bjork
    Kirchhoff, Tomas
    Offit, Kenneth
    Piedmonte, Marion
    Rodriguez, Gustavo
    Small, Laurie
    Boggess, John
    Blank, Stephanie
    Basil, Jack
    Azodi, Masoud
    Toland, Amanda Ewart
    Montagna, Marco
    Tognazzo, Silvia
    Agata, Simona
    Imyanitov, Evgeny
    Janavicius, Ramunas
    Lazaro, Conxi
    Blanco, Ignacio
    Pharoah, Paul D P
    Sucheston, Lara
    Karlan, Beth Y
    Walsh, Christine S
    Olah, Edith
    Bozsik, Aniko
    Teo, Soo-Hwang
    Seldon, Joyce L
    Beattie, Mary S
    van Rensburg, Elizabeth J
    Sluiter, Michelle D
    Diez, Orland
    Schmutzler, Rita K
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Ruehl, Ina
    Varon-Mateeva, Raymonda
    Kast, Karin
    Deissler, Helmut
    Niederacher, Dieter
    Arnold, Norbert
    Gadzicki, Dorothea
    Schönbuchner, Ines
    Caldes, Trinidad
    de la Hoya, Miguel
    Nevanlinna, Heli
    Aittomäki, Kristiina
    Dumont, Martine
    Chiquette, Jocelyne
    Tischkowitz, Marc
    Chen, Xiaoqing
    Beesley, Jonathan
    Spurdle, Amanda B
    Neuhausen, Susan L
    Chun Ding, Yuan
    Fredericksen, Zachary
    Wang, Xianshu
    Pankratz, Vernon S
    Couch, Fergus
    Simard, Jacques
    Easton, Douglas F
    Chenevix-Trench, Georgia
    Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers2011In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 16, p. 3304-3321Article in journal (Refereed)
    Abstract [en]

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

  • 4. Barekati, Zeinab
    et al.
    Radpour, Ramin
    Kohler, Corina
    Zhang, Bei
    Toniolo, Paolo
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lv, Qing
    Zheng, Hong
    Zhong, Xiao Yan
    Methylation profile of TP53 regulatory pathway and mtDNA alterations in breast cancer patients lacking TP53 mutations2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 15, p. 2936-2946Article in journal (Refereed)
    Abstract [en]

    The present study investigated promoter hypermethylation of TP53 regulatory pathways providing a potential link between epigenetic changes and mitochondrial DNA (mtDNA) alterations in breast cancer patients lacking a TP53 mutation. The possibility of using the cancer-specific alterations in serum samples as a blood-based test was also explored. Triple-matched samples (cancerous tissues, matched adjacent normal tissues and serum samples) from breast cancer patients were screened for TP53 mutations, and the promoter methylation profile of P14(ARF), MDM2, TP53 and PTEN genes was analyzed as well as mtDNA alterations, including D-loop mutations and mtDNA content. In the studied cohort, no mutation was found in TP53 (DNA-binding domain). Comparison of P14(ARF) and PTEN methylation patterns showed significant hypermethylation levels in tumor tissues (P < 0.05 and <0.01, respectively) whereas the TP53 tumor suppressor gene was not hypermethylated (P < 0.511). The proportion of PTEN methylation was significantly higher in serum than in the normal tissues and it has a significant correlation to tumor tissues (P < 0.05). mtDNA analysis revealed 36.36% somatic and 90.91% germline mutations in the D-loop region and also significant mtDNA depletion in tumor tissues (P < 0.01). In addition, the mtDNA content in matched serum was significantly lower than in the normal tissues (P < 0.05). These data can provide an insight into the management of a therapeutic approach based on the reversal of epigenetic silencing of the crucial genes involved in regulatory pathways of the tumor suppressor TP53. Additionally, release of significant aberrant methylated PTEN in matched serum samples might represent a promising biomarker for breast cancer.

  • 5. Barrdahl, Myrto
    et al.
    Canzian, Federico
    Joshi, Amit D.
    Travis, Ruth C.
    Chang-Claude, Jenny
    Auer, Paul L.
    Gapstur, Susan M.
    Gaudet, Mia
    Diver, W. Ryan
    Henderson, Brian E.
    Haiman, Christopher A.
    Schumacher, Fredrick R.
    Le Marchand, Loic
    Berg, Christine D.
    Chanock, Stephen J.
    Hoover, Robert N.
    Rudolph, Anja
    Ziegler, Regina G.
    Giles, Graham G.
    Baglietto, Laura
    Severi, Gianluca
    Hankinson, Susan E.
    Lindstroem, Sara
    Willet, Walter
    Hunter, David J.
    Buring, Julie E.
    Lee, I-Min
    Zhang, Shumin
    Dossus, Laure
    Cox, David G.
    Khaw, Kay-Tee
    Lund, Eiliv
    Naccarati, Alessio
    Peeters, Petra H.
    Ramon Quiros, J.
    Riboli, Elio
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Trichopoulos, Dimitrios
    Prentice, Ross L.
    Kraft, Peter
    Kaaks, Rudolf
    Campa, Daniele
    Post-G WAS gene-environment interplay in breast cancer: results from the Breast and Prostate Cancer Cohort Consortium and a meta-analysis on 79 000 women2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 19, p. 5260-5270Article in journal (Refereed)
    Abstract [en]

    We studied the interplay between 39 breast cancer (BC) risk SNPs and established BC risk (body mass index, height, age at menarche, parity, age at menopause, smoking, alcohol and family history of BC) and prognostic factors (TNM stage, tumor grade, tumor size, age at diagnosis, estrogen receptor status and progesterone receptor status) as joint determinants of BC risk. We used a nested case-control design within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), with 16 285 BC cases and 19 376 controls. We performed stratified analyses for both the risk and prognostic factors, testing for heterogeneity for the risk factors, and case-case comparisons for differential associations of polymorphisms by subgroups of the prognostic factors. We analyzed multiplicative interactions between the SNPs and the risk factors. Finally, we also performed a meta-analysis of the interaction ORs from BPC3 and the Breast Cancer Association Consortium. After correction for multiple testing, no significant interaction between the SNPs and the established risk factors in the BPC3 study was found. The meta-analysis showed a suggestive interaction between smoking status and SLC4A7-rs4973768 (P-interaction = 8.84 x 10(-4)) which, although not significant after considering multiple comparison, has a plausible biological explanation. In conclusion, in this study of up to almost 79 000 women we can conclusively exclude any novel major interactions between genome-wide association studies hits and the epidemiologic risk factors taken into consideration, but we propose a suggestive interaction between smoking status and SLC4A7-rs4973768 that if further replicated could help our understanding in the etiology of BC.

  • 6. Bento-Abreu, Andre
    et al.
    Jager, Gunilla
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Swinnen, Bart
    Rué, Laura
    Hendrickx, Stijn
    Jones, Ashley
    Staats, Kim A.
    Taes, Ines
    Eykens, Caroline
    Nonneman, Annelies
    Nuyts, Rik
    Timmers, Mieke
    Silva, Lara
    Chariot, Alain
    Nguyen, Laurent
    Ravits, John
    Lemmens, Robin
    Cabooter, Deirdre
    Van Den Bosch, Ludo
    Van Damme, Philip
    Al-Chalabi, Ammar
    Bystrom, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Robberecht, Wim
    Elongator subunit 3 (ELP3) modifies ALS through tRNA modification.2018In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 7, p. 1276-1289Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder of which the progression is influenced by several disease-modifying factors. Here, we investigated ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines, as one of such ALS disease modifiers. ELP3 attenuated the axonopathy of a mutant SOD1, as well as of a mutant C9orf72 ALS zebrafish model. Furthermore, the expression of ELP3 in the SOD1G93A mouse extended the survival and attenuated the denervation in this model. Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U and increased abundance of insoluble mutant SOD1, which was reverted by exogenous ELP3 expression. Interestingly, the expression of ELP3 in the motor cortex of ALS patients was reduced and correlated with mcm5s2U levels. Our results demonstrate that ELP3 is a modifier of ALS and suggest a link between tRNA modification and neurodegeneration.

  • 7. Berndt, Sonja I
    et al.
    Sampson, Joshua
    Yeager, Meredith
    Jacobs, Kevin B
    Wang, Zhaoming
    Hutchinson, Amy
    Chung, Charles
    Orr, Nick
    Wacholder, Sholom
    Chatterjee, Nilanjan
    Yu, Kai
    Kraft, Peter
    Feigelson, Heather Spencer
    Thun, Michael J
    Diver, W Ryan
    Albanes, Demetrius
    Virtamo, Jarmo
    Weinstein, Stephanie
    Schumacher, Fredrick R
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Valeri, Antoine
    Andriole, Gerald L
    Crawford, E David
    Haiman, Christopher
    Henderson, Brian
    Kolonel, Laurence
    Le Marchand, Loic
    Siddiq, Afshan
    Riboli, Elio
    Travis, Ruth C
    Kaaks, Rudolf
    Isaacs, William
    Isaacs, Sarah
    Wiley, Kathleen E
    Gronberg, Henrik
    Wiklund, Fredrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Xu, Jianfeng
    Zheng, S Lilly
    Sun, Jielin
    Vatten, Lars J
    Hveem, Kristian
    Njølstad, Inger
    Gerhard, Daniela S
    Tucker, Margaret
    Hayes, Richard B
    Hoover, Robert N
    Fraumeni, Joseph F
    Hunter, David J
    Thomas, Gilles
    Chanock, Stephen J
    Large-scale fine mapping of the HNF1B locus and prostate cancer risk2011In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 16, p. 3322-3329Article in journal (Refereed)
    Abstract [en]

    Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.

  • 8.
    Birve, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Neuwirth, Christoph
    Weber, Markus
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Jonsson, Per Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 21, p. 4201-4206Article in journal (Refereed)
    Abstract [en]

    More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS-associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reported.

  • 9. Blauw, Hylke M
    et al.
    Al-Chalabi, Ammar
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    van Vught, Paul W J
    Diekstra, Frank P
    van Es, Michael A
    Saris, Christiaan G J
    Groen, Ewout J N
    van Rheenen, Wouter
    Koppers, Max
    Van't Slot, Ruben
    Strengman, Eric
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G
    Kiemeney, Lambertus A
    Vermeulen, Sita H M
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Waibel, Stefan
    Meyer, Thomas
    Cronin, Simon
    McLaughlin, Russell L
    Hardiman, Orla
    Sapp, Peter C
    Tobin, Martin D
    Wain, Louise V
    Tomik, Barbara
    Slowik, Agnieszka
    Lemmens, Robin
    Rujescu, Dan
    Schulte, Claudia
    Gasser, Thomas
    Brown, Robert H
    Landers, John E
    Robberecht, Wim
    Ludolph, Albert C
    Ophoff, Roel A
    Veldink, Jan H
    van den Berg, Leonard H
    A large genome scan for rare CNVs in amyotrophic lateral sclerosis2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 20, p. 4091-4099Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.

  • 10. Brockmann, Sarah J.
    et al.
    Freischmidt, Axel
    Oeckl, Patrick
    Müller, Kathrin
    Ponna, Srinivas K.
    Helferich, Anika M.
    Paone, Christoph
    Reinders, Jörg
    Kojer, Kerstin
    Orth, Michael
    Jokela, Manu
    Auranen, Mari
    Udd, Bjarne
    Hermann, Andreas
    Danzer, Karin M.
    Lichtner, Peter
    Walther, Paul
    Ludolph, Albert C.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Otto, Markus
    Kursula, Petri
    Just, Steffen
    Weishaupt, Jochen H.
    CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency2018In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 4, p. 706-715Article in journal (Refereed)
    Abstract [en]

    Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p. R15L and p. G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p. P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p. R15L and p. G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p. R15L, but not of CHCHD10 p. G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p. G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p. P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.

  • 11. Canzian, Federico
    et al.
    Cox, David G
    Setiawan, V Wendy
    Stram, Daniel O
    Ziegler, Regina G
    Dossus, Laure
    Beckmann, Lars
    Blanché, Hélène
    Barricarte, Aurelio
    Berg, Christine D
    Bingham, Sheila
    Buring, Julie
    Buys, Saundra S
    Calle, Eugenia E
    Chanock, Stephen J
    Clavel-Chapelon, Françoise
    Delancey, John Oliver L
    Diver, W Ryan
    Dorronsoro, Miren
    Haiman, Christopher A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Hunter, David J
    Hüsing, Anika
    Isaacs, Claudine
    Khaw, Kay-Tee
    Kolonel, Laurence N
    Kraft, Peter
    Le Marchand, Loïc
    Lund, Eiliv
    Overvad, Kim
    Panico, Salvatore
    Peeters, Petra H M
    Pollak, Michael
    Thun, Michael J
    Tjønneland, Anne
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Yeager, Meredith
    Hoover, Robert N
    Riboli, Elio
    Thomas, Gilles
    Henderson, Brian E
    Kaaks, Rudolf
    Feigelson, Heather Spencer
    Comprehensive analysis of common genetic variation in 61 genes related to steroid hormone and insulin-like growth factor-I metabolism and breast cancer risk in the NCI breast and prostate cancer cohort consortium.2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 19, p. 3873-84Article in journal (Refereed)
    Abstract [en]

    There is extensive evidence that increases in blood and tissue concentrations of steroid hormones and of insulin-like growth factor I (IGF-I) are associated with breast cancer risk. However, studies of common variation in genes involved in steroid hormone and IGF-I metabolism have yet to provide convincing evidence that such variants predict breast cancer risk. The Breast and Prostate Cancer Cohort Consortium (BPC3) is a collaboration of large US and European cohorts. We genotyped 1416 tagging single nucleotide polymorphisms (SNPs) in 37 steroid hormone metabolism genes and 24 IGF-I pathway genes in 6292 cases of breast cancer and 8135 controls, mostly Caucasian, postmenopausal women from the BPC3. We also imputed 3921 additional SNPs in the regions of interest. None of the SNPs tested was significantly associated with breast cancer risk, after correction for multiple comparisons. The results remained null when cases and controls were stratified by age at diagnosis/recruitment, advanced or nonadvanced disease, body mass index, with or without in situ cases; or restricted to Caucasians. Among 770 estrogen receptor-negative cases, an SNP located 3' of growth hormone receptor (GHR) was marginally associated with increased risk after correction for multiple testing (P(trend) = 1.5 × 10(-4)). We found no significant overall associations between breast cancer and common germline variation in 61 genes involved in steroid hormone and IGF-I metabolism in this large, comprehensive study. Although previous studies have shown that variations in these genes can influence endogenous hormone levels, the magnitude of the effect of single SNPs does not appear to be sufficient to alter breast cancer risk.

  • 12. Cooper, Helen M.
    et al.
    Yang, Yang
    Ylikallio, Emil
    Khairullin, Rafil
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia.
    Woldegebriel, Rosa
    Lin, Kai-Lan
    Euro, Liliya
    Palin, Eino
    Wolf, Alexander
    Trokovic, Ras
    Isohanni, Pirjo
    Kaakkola, Seppo
    Auranen, Mari
    Lönnqvist, Tuula
    Wanrooij, Sjoerd
    Tyynismaa, Henna
    ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 8, p. 1432-1443Article in journal (Refereed)
    Abstract [en]

    De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.

  • 13.
    Dubbaka Venu, Pradeep Reddy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zheng, Wenjing
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liang, Shawn
    Hämäläinen, Tuula
    Tohonen, Virpi
    Ogawa, Wataru
    Noda, Tetsuo
    Volarevic, Sinisa
    Huhtaniemi, Ilpo
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 15, p. 2813-2824Article in journal (Refereed)
    Abstract [en]

    The molecular mechanisms that control reproductive aging and menopausal age in females are poorly understood. Here, we provide genetic evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) signaling in oocytes preserves reproductive lifespan by maintaining the survival of ovarian primordial follicles. In mice lacking the PDK1-encoding gene Pdk1 in oocytes, the majority of primordial follicles are depleted around the onset of sexual maturity, causing premature ovarian failure (POF) during early adulthood. We further showed that suppressed PDK1-Akt-p70 S6 kinase 1 (S6K1)-ribosomal protein S6 (rpS6) signaling in oocytes appears to be responsible for the loss of primordial follicles, and mice lacking the Rps6 gene in oocytes show POF similar to that in Pdk1-deficient mice. In combination with our earlier finding that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in oocytes suppresses follicular activation, we have now pinpointed the molecular network involving phosphatidylinositol 3 kinase (PI3K)/PTEN-PDK1 signaling in oocytes that controls the survival, loss and activation of primordial follicles, which together determine reproductive aging and the length of reproductive life in females. Underactivation or overactivation of this signaling pathway in oocytes is shown to cause pathological conditions in the ovary, including POF and infertility.

  • 14.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Carlsson, Anna
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Minde, Jan
    Toolanen, Göran
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Solders, Göran
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.2004In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 13, no 8, p. 799-805Article in journal (Refereed)
    Abstract [en]

    Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

  • 15. Ek, Weronica E.
    et al.
    Tobi, Elmar W.
    Ahsan, Muhammad
    Lampa, Erik
    Ponzi, Erica
    Kyrtopoulos, Soterios A.
    Georgiadis, Panagiotis
    Lumey, L. H.
    Heijmans, Bastiaan T.
    Botsivali, Maria
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Karlsson, Torgny
    Rask-Andersen, Mathias
    Palli, Domenico
    Ingelsson, Erik
    Hedman, Åsa K.
    Nilsson, Lena M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Vineis, Paolo
    Lind, Lars
    Flanagan, James M.
    Johansson, Åsa
    Tea and coffee consumption in relation to DNA methylation in four European cohorts2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 16, p. 3221-3231Article in journal (Refereed)
    Abstract [en]

    Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea has been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation.To investigate if DNA methylation in blood is associated with coffee and tea consumption we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed.After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated in men or in the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.

  • 16.
    Eschbach, Judith
    et al.
    Neurology, Ulm University, Germany.
    Schwalenstocker, Birgit
    Neurology, Ulm University, Germany.
    Soyal, Selma M.
    Pharmacology, Paracelsus Medical University, Salzburg, Austria.
    Bayer, Hanna
    Neurology, Ulm University, Germany.
    Wiesner, Diana
    Neurology, Ulm University, Germany.
    Akimoto, Chizuru
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Meyer, Thomas
    Neurology, Charité University Hospital, Berlin, Germany.
    Dupuis, Luc
    INSERM, Strasbourg, France ; Faculté de Médecine, Université de Strasbourg, , France.
    Danzer, Karin M.
    Neurology, Ulm University, Germany.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Neurology, Ulm University, Germany.
    Witting, Anke
    Neurology, Ulm University, Germany.
    Ludolph, Albert C.
    Neurology, Ulm University, Germany.
    Patsch, Wolfgang
    Pharmacology, Paracelsus Medical University, Salzburg, Austria.
    Weydt, Patrick
    Neurology, Ulm University, Germany.
    PGC-1 is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis2013In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 17, p. 3477-3484Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 35 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1 leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.

  • 17. Figueroa, Jonine D.
    et al.
    Middlebrooks, Candace D.
    Banday, A. Rouf
    Ye, Yuanqing
    Garcia-Closas, Montserrat
    Chatterjee, Nilanjan
    Koutros, Stella
    Kiemeney, Lambertus A.
    Rafnar, Thorunn
    Bishop, Timothy
    Furberg, Helena
    Matullo, Giuseppe
    Golka, Klaus
    Gago-Dominguez, Manuela
    Taylor, Jack A.
    Fletcher, Tony
    Siddiq, Afshan
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Dinney, Colin P.
    Malats, Nuria
    Baris, Dalsu
    Purdue, Mark P.
    Jacobs, Eric J.
    Albanes, Demetrius
    Wang, Zhaoming
    Chung, Charles C.
    Vermeulen, Sita H.
    Aben, Katja K.
    Galesloot, Tessel E.
    Thorleifsson, Gudmar
    Sulem, Patrick
    Stefansson, Kari
    Kiltie, Anne E.
    Harland, Mark
    Teo, Mark
    Offit, Kenneth
    Vijai, Joseph
    Bajorin, Dean
    Kopp, Ryan
    Fiorito, Giovanni
    Guarrera, Simonetta
    Sacerdote, Carlotta
    Selinski, Silvia
    Hengstler, Jan G.
    Gerullis, Holger
    Ovsiannikov, Daniel
    Blaszkewicz, Meinolf
    Esteban Castelao, Jose
    Calaza, Manuel
    Martinez, Maria Elena
    Cordeiro, Patricia
    Xu, Zongli
    Panduri, Vijayalakshmi
    Kumar, Rajiv
    Gurzau, Eugene
    Koppova, Kvetoslava
    Bueno-De-Mesquita, H. Bas
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Francoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth C.
    Tjonneland, Anne
    Brennan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Stern, Marianna C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Jeppson, Rebecca P.
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Turman, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Kamat, Ashish M.
    Zhang, Liren
    Gong, Yilei
    Pu, Xia
    Hutchinson, Amy
    Burdett, Laurie
    Wheeler, William A.
    Karagas, Margaret R.
    Johnson, Alison
    Schned, Alan
    Hosain, G. M. Monawar
    Schwenn, Molly
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Andriole, Gerald, Jr.
    Grubb, Robert, III
    Black, Amanda
    Diver, W. Ryan
    Gapstur, Susan M.
    Weinstein, Stephanie
    Virtamo, Jarmo
    Haiman, Christopher A.
    Landi, Maria Teresa
    Caporaso, Neil E.
    Fraumeni, Joseph F., Jr.
    Vineis, Paolo
    Wu, Xifeng
    Chanock, Stephen J.
    Silverman, Debra T.
    Prokunina-Olsson, Ludmila
    Rothman, Nathaniel
    Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 6, p. 1203-1214Article in journal (Refereed)
    Abstract [en]

    Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

  • 18. Figueroa, Jonine D.
    et al.
    Ye, Yuanqing
    Siddiq, Afshan
    Garcia-Closas, Montserrat
    Chatterjee, Nilanjan
    Prokunina-Olsson, Ludmila
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Dinney, Colin P.
    Malats, Nuria
    Baris, Dalsu
    Purdue, Mark
    Jacobs, Eric J.
    Albanes, Demetrius
    Wang, Zhaoming
    Deng, Xiang
    Chung, Charles C.
    Tang, Wei
    Bueno-De-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Frangoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth
    Tjonneland, Anne
    Brenan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Rodabough, Rebecca
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Chen, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Kamat, Ashish M.
    Lerner, Seth P.
    Grossman, H. Barton
    Lin, Jie
    Gu, Jian
    Pu, Xia
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Schwenn, Molly
    Karagas, Margaret R.
    Johnson, Alison
    Schned, Alan
    Armenti, Karla R.
    Hosain, G. M.
    Andriole, Gerald, Jr.
    Grubb, Robert, III
    Black, Amanda
    Diver, W. Ryan
    Gapstur, Susan M.
    Weinstein, Stephanie J.
    Virtamo, Jarmo
    Haiman, Chris A.
    Landi, Maria T.
    Caporaso, Neil
    Fraumeni, Joseph F., Jr.
    Vineis, Paolo
    Wu, Xifeng
    Silverman, Debra T.
    Chanock, Stephen
    Rothman, Nathaniel
    Genome-wide association study identifies multiple loci associated with bladder cancer risk2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 5, p. 1387-1398Article in journal (Refereed)
    Abstract [en]

    andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

  • 19. Fogh, Isabella
    et al.
    Ratti, Antonia
    Gellera, Cinzia
    Lin, Kuang
    Tiloca, Cinzia
    Moskvina, Valentina
    Corrado, Lucia
    Soraru, Gianni
    Cereda, Cristina
    Corti, Stefania
    Gentilini, Davide
    Calini, Daniela
    Castellotti, Barbara
    Mazzini, Letizia
    Querin, Giorgia
    Gagliardi, Stella
    Del Bo, Roberto
    Conforti, Francesca L.
    Siciliano, Gabriele
    Inghilleri, Maurizio
    Sacca, Francesco
    Bongioanni, Paolo
    Penco, Silvana
    Corbo, Massimo
    Sorbi, Sandro
    Filosto, Massimiliano
    Ferlini, Alessandra
    Di Blasio, Anna M.
    Signorini, Stefano
    Shatunov, Aleksey
    Jones, Ashley
    Shaw, Pamela J.
    Morrison, Karen E.
    Farmer, Anne E.
    Van Damme, Philip
    Robberecht, Wim
    Chi, Adriano
    Traynor, Bryan J.
    Sendtner, Michael
    Melki, Judith
    Meininger, Vincent
    Hardiman, Orla
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Leigh, Nigel P.
    Glass, Jonathan D.
    Overste, Daniel
    Diekstra, Frank P.
    Veldink, Jan H.
    van Es, Michael A.
    Shaw, Christopher E.
    Weale, Michael E.
    Lewis, Cathryn M.
    Williams, Julie
    Brown, Robert H.
    Landers, John E.
    Ticozzi, Nicola
    Ceroni, Mauro
    Pegoraro, Elena
    Comi, Giacomo P.
    DAlfonso, Sandra
    van den Berg, Leonard H.
    Taroni, Franco
    Al-Chalabi, Ammar
    Powell, John
    Silani, Vincenzo
    A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 8, p. 2220-2231Article in journal (Refereed)
    Abstract [en]

    Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

  • 20. Friedrich, Felix W.
    et al.
    Wilding, Brendan R.
    Reischmann, Silke
    Crocini, Claudia
    Lang, Patrick
    Charron, Philippe
    Mueller, Oliver J.
    McGrath, Meagan J.
    Vollert, Ingra
    Hansen, Arne
    Linke, Wolfgang A.
    Hengstenberg, Christian
    Bonne, Gisele
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wichter, Thomas
    Madeira, Hugo
    Arbustini, Eloisa
    Eschenhagen, Thomas
    Mitchell, Christina A.
    Isnard, Richard
    Carrier, Lucie
    Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 14, p. 3237-3254Article in journal (Refereed)
    Abstract [en]

    Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in 40 of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459CA/C153X and c.827GC/C276S). Whereas the c.459CA variant was associated with muscle weakness in some patients, the c.134delA and c.827GC variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.

  • 21. Goris, An
    et al.
    van Setten, Jessica
    Diekstra, Frank
    Ripke, Stephan
    Patsopoulos, Nikolaos A.
    Sawcer, Stephen J.
    van Es, Michael
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Melki, Judith
    Meininger, Vincent
    Hardiman, Orla
    Landers, John E.
    Brown, Robert H., Jr.
    Shatunov, Aleksey
    Leigh, Nigel
    Al-Chalabi, Ammar
    Shaw, Christopher E.
    Traynor, Bryan J.
    Chio, Adriano
    Restagno, Gabriella
    Mora, Gabriele
    Ophoff, Roel A.
    Oksenberg, Jorge R.
    Van Damme, Philip
    Compston, Alastair
    Robberecht, Wim
    Dubois, Benedicte
    van den Berg, Leonard H.
    De Jager, Philip L.
    Veldink, Jan H.
    de Bakker, Paul I. W.
    No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 7, p. 1916-1922Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.

  • 22.
    Graffmo, Karin S.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis2013In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 1, p. 51-60Article in journal (Refereed)
    Abstract [en]

    A common cause of amyotrophic lateral sclerosis (ALS) is mutations in the gene encoding superoxide dismutase-1. There is evolving circumstantial evidence that the wild-type protein can also be neurotoxic and that it may more generally be involved in the pathogenesis of ALS. To test this proposition more directly, we generated mice that express wild-type human superoxide dismutase-1 at a rate close to that of mutant superoxide dismutase-1 in the commonly studied G93A transgenic model. These mice developed an ALS-like syndrome and became terminally ill after around 370 days. The loss of spinal ventral neurons was similar to that in the G93A and other mutant superoxide dismutase-1 models, and large amounts of aggregated superoxide dismutase-1 were found in spinal cords, but also in the brain. The findings show that wild-type human superoxide dismutase-1 has the ability to cause ALS in mice, and they support the hypothesis of a more general involvement of the protein in the disease in humans.

  • 23. Haworth, Simon
    et al.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
    van der Tas, Justin T
    Vucic, Strahinja
    Medina-Gomez, Carolina
    Yakimov, Victor
    Feenstra, Bjarke
    Shaffer, John R
    Lee, Myoung Keun
    Standl, Marie
    Thiering, Elisabeth
    Wang, Carol
    Bønnelykke, Klaus
    Waage, Johannes
    Jessen, Leon Eyrich
    Nørrisgaard, Pia Elisabeth
    Joro, Raimo
    Seppälä, Ilkka
    Raitakari, Olli
    Dudding, Tom
    Grgic, Olja
    Ongkosuwito, Edwin
    Vierola, Anu
    Eloranta, Aino-Maija
    West, Nicola X
    Thomas, Steven J
    McNeil, Daniel W
    Levy, Steven M
    Slayton, Rebecca
    Nohr, Ellen A
    Lehtimäki, Terho
    Lakka, Timo
    Bisgaard, Hans
    Pennell, Craig
    Kühnisch, Jan
    Marazita, Mary L
    Melbye, Mads
    Geller, Frank
    Rivadeneira, Fernando
    Wolvius, Eppo B
    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, Malmö 202 13, Sweden; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Timpson, Nicholas J
    Consortium-based genome-wide meta-analysis for childhood dental caries traits2018In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 17, p. 3113-3127Article in journal (Refereed)
    Abstract [en]

    Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

  • 24. Hilton, Emma N
    et al.
    Manson, Forbes D C
    Urquhart, Jill E
    Johnston, Jennifer J
    Slavotinek, Anne M
    Hedera, Peter
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nordgren, Ann
    Biesecker, Leslie G
    Black, Graeme C M
    Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination.2007In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 16, no 14, p. 1773-1782Article in journal (Refereed)
    Abstract [en]

    Oculofaciocardiodental (OFCD) syndrome is an X-linked male lethal condition encompassing cardiac septal defects, as well as ocular and dental anomalies. The gene mutated in OFCD syndrome, the BCL-6 corepressor (BCOR), is part of a transcriptional repression complex whose transcriptional targets remain largely unknown. We reviewed cases of OFCD syndrome and identified patients exhibiting defective lateralization including dextrocardia, asplenia and intestinal malrotation, suggesting that BCOR is required in normal laterality determination. To study the function of BCOR, we used morpholino oligonucleotides (MOs) to knockdown expression of xtBcor in Xenopus tropicalis, thus creating an animal model for OFCD syndrome. The resulting tadpoles had cardiac and ocular features characteristic of OFCD syndrome. Reversed cardiac orientation and disorganized gut patterning were seen when MOs were injected into the left side of embryos, demonstrating a left-sided requirement for xtBcor in lateral determination in Xenopus. Ocular defects displayed no left-right bias and included anterior and posterior segment disorders such as microphthalmia and coloboma. Expression of xtPitx2c was shown to be downregulated when xtBcor was depleted. This identifies a pathway in which xtBcor is required for lateral specification, a process intrinsically linked to correct cardiac septal development.

  • 25.
    Holmberg, Monica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Johansson, Jenni
    Forsgren, Lars
    Heijbel, Jan
    Sandgren, Ola
    Holmgren, Gösta
    Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.11995In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 4, no 8, p. 1441-1445Article in journal (Refereed)
    Abstract [en]

    We present linkage analysis on a large Swedish five-generation family of 15 affected individuals with autosomal dominant cerebellar ataxia (ADCA) associated with retinal degeneration and anticipation, Common clinical signs in this family include ataxia, dysarthria and severely impaired vision with the phenotype ADCA type II, Different subtypes of ADCA have proven difficult to classify clinically due to extensive phenotypic variability within and between families. Genetic analysis of a number of ADCA type I families shows that heterogeneity exists also genetically, During the last few years several types of ADCA type I have been localized and to date six genetically distinct forms have been identified including SCA1 (6p), SCA2 (12q), SCA3 and Machado-Joseph disease (MJD) (14q), SCA4 (16q), and finally SCA5 (11), We performed a genome-wide search of the Swedish ADCA type II family using a total of 270 microsatellite markers, Positive lod scores were obtained with a number of microsatellite markers located on chromosome 3p12-p21.1. Three markers gave lod scores over 3 with a maximum lod score of 4.53 achieved with the marker D3S1600. The ADCA type II gene could be restricted to a region of 32 cM by the markers D3S1547 and D3S1274.

  • 26.
    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.

  • 27. Kanoni, Stavroula
    et al.
    Masca, Nicholas G D
    Stirrups, Kathleen E
    Varga, Tibor V
    Warren, Helen R
    Scott, Robert A
    Southam, Lorraine
    Zhang, Weihua
    Yaghootkar, Hanieh
    Müller-Nurasyid, Martina
    Couto Alves, Alexessander
    Strawbridge, Rona J
    Lataniotis, Lazaros
    An Hashim, Nikman
    Besse, Céline
    Boland, Anne
    Braund, Peter S
    Connell, John M
    Dominiczak, Anna
    Farmaki, Aliki-Eleni
    Franks, Stephen
    Grallert, Harald
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karaleftheri, Maria
    Keinänen-Kiukaanniemi, Sirkka
    Matchan, Angela
    Pasko, Dorota
    Peters, Annette
    Poulter, Neil
    Rayner, Nigel W
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö , Sweden.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sabater-Lleal, Maria
    Sennblad, Bengt
    Sever, Peter
    Shields, Denis
    Silveira, Angela
    Stanton, Alice V
    Strauch, Konstantin
    Tomaszewski, Maciej
    Tsafantakis, Emmanouil
    Waldenberger, Melanie
    Blakemore, Alexandra I F
    Dedoussis, George
    Escher, Stefan A
    Kooner, Jaspal S
    McCarthy, Mark I
    Palmer, Colin N A
    Hamsten, Anders
    Caulfield, Mark J
    Frayling, Timothy M
    Tobin, Martin D
    Jarvelin, Marjo-Riitta
    Zeggini, Eleftheria
    Gieger, Christian
    Chambers, John C
    Wareham, Nick J
    Munroe, Patricia B
    Franks, Paul W
    Samani, Nilesh J
    Deloukas, Panos
    Analysis with the exome array identifies multiple new independent variants in lipid loci2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 18, p. 4094-4106Article in journal (Refereed)
    Abstract [en]

    It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

  • 28. Lee, Teresa
    et al.
    Li, Yun R
    Ingre, Caroline
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Weber, Markus
    Grehl, Torsten
    Gredal, Ole
    de Carvalho, Mamede
    Meyer, Thomas
    Tysnes, Ole-Björn
    Auburger, Georg
    Gispert, Suzana
    Bonini, Nancy M
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gitler, Aaron D
    Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients2011In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 9, p. 1697-1700Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 × 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.

  • 29. Lind, L
    et al.
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wahlin, A
    Eriksson, M
    Nilsson-Sojka, B
    Sikström, C
    Holmgren, G
    Localization of the gene for congenital dyserythropoietic anemia type III, CDAN3, to chromosome 15q21-q25.1995In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 4, no 1, p. 109-12Article in journal (Refereed)
    Abstract [en]

    Congenital dyserythropoietic anemia, type III (CDA III) is a rare autosomal dominant disorder characterized by macrocytic anemia, bone marrow erythroid hyperplasia and giant multinucleate erythroblasts. We have genetically characterized a large Swedish family in which the concurrence of CDA III and myeloma or benign monoclonal gammopathy is significantly higher than expected and have found that the causative genetic defect for CDA III maps to an 11 cM interval within 15q21-q25.

  • 30. Lo, Min-Tzu
    et al.
    Wang, Yunpeng
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Department of Radiology, Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA 92037, USA.
    Sanyal, Nilotpal
    Fan, Chun-Chieh
    Smeland, Olav B.
    Schork, Andrew
    Holland, Dominic
    Hinds, David A.
    Tung, Joyce Y.
    Andreassen, Ole A.
    Dale, Anders M.
    Chen, Chi-Hua
    Modeling prior information of common genetic variants improves gene discovery for neuroticism2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 22, p. 4530-4539Article in journal (Refereed)
    Abstract [en]

    Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remain unclear. Inconsistent genetic variants identified by different genome-wide association studies (GWAS) may be attributable to low statistical power. We proposed a novel framework to improve the power for gene discovery by incorporating prior information of single nucleotide polymorphisms (SNPs) and combining two relevant existing tools, relative enrichment score (RES) and conditional false discovery rate (FDR). Here, SNP's conditional FDR was estimated given its RES based on SNP prior information including linkage disequilibrium (LD)-weighted genic annotation scores, total LD scores and heterozygosity. A known significant locus in chromosome 8p was excluded before estimating FDR due to long-range LD structure. Only one significant LD-independent SNP was detected by analyses of unconditional FDR and traditional GWAS in the discovery sample (N = 59 225), and notably four additional SNPs by conditional FDR. Three of the five SNPs, all identified by conditional FDR, were replicated (P < 0.05) in an independent sample (N = 170 911). These three SNPs are located in intronic regions of CADM2, LINGO2 and EP300 which have been reported to be associated with autism, Parkinson's disease and schizophrenia, respectively. Our approach using a combination of RES and conditional FDR improved power of traditional GWAS for gene discovery providing a useful framework for the analysis of GWAS summary statistics by utilizing SNP prior information, and helping to elucidate the links between neuroticism and complex diseases from a genetic perspective.

  • 31. Machiela, Mitchell J.
    et al.
    Lan, Qing
    Slager, Susan L.
    Vermeulen, Roel C. H.
    Teras, Lauren R.
    Camp, Nicola J.
    Cerhan, James R.
    Spinelli, John J.
    Wang, Sophia S.
    Nieters, Alexandra
    Vijai, Joseph
    Yeager, Meredith
    Wang, Zhaoming
    Ghesquieres, Herve
    Mckay, James
    Conde, Lucia
    de Bakker, Paul I. W.
    Cox, David G.
    Burdett, Laurie
    Monnereau, Alain
    Flowers, Christopher R.
    De Roos, Anneclaire J.
    Brooks-Wilson, Angela R.
    Giles, Graham G.
    Melbye, Mads
    Gu, Jian
    Jackson, Rebecca D.
    Kane, Eleanor
    Purdue, Mark P.
    Vajdic, Claire M.
    Albanes, Demetrius
    Kelly, Rachel S.
    Zucca, Mariagrazia
    Bertrand, Kimberly A.
    Zeleniuch-Jacquotte, Anne
    Lawrence, Charles
    Hutchinson, Amy
    Zhi, Degui
    Habermann, Thomas M.
    Link, Brian K.
    Novak, Anne J.
    Dogan, Ahmet
    Asmann, Yan W.
    Liebow, Mark
    Thompson, Carrie A.
    Ansell, Stephen M.
    Witzig, Thomas E.
    Tilly, Herve
    Haioun, Corinne
    Molina, Thierry J.
    Hjalgrim, Henrik
    Glimelius, Bengt
    Adami, Hans-Olov
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bracci, Paige M.
    Riby, Jacques
    Smith, Martyn T.
    Holly, Elizabeth A.
    Cozen, Wendy
    Hartge, Patricia
    Morton, Lindsay M.
    Severson, Richard K.
    Tinker, Lesley F.
    North, Kari E.
    Becker, Nikolaus
    Benavente, Yolanda
    Boffetta, Paolo
    Brennan, Paul
    Foretova, Lenka
    Maynadie, Marc
    Staines, Anthony
    Lightfoot, Tracy
    Crouch, Simon
    Smith, Alex
    Roman, Eve
    Diver, W. Ryan
    Offit, Kenneth
    Zelenetz, Andrew
    Klein, Robert J.
    Villano, Danylo J.
    Zheng, Tongzhang
    Zhang, Yawei
    Holford, Theodore R.
    Turner, Jenny
    Southey, Melissa C.
    Clavel, Jacqueline
    Virtamo, Jarmo
    Weinstein, Stephanie
    Riboli, Elio
    Vineis, Paolo
    Kaaks, Rudolph
    Boeing, Heiner
    Tjonneland, Anne
    Angelucci, Emanuele
    Di Lollo, Simonetta
    Rais, Marco
    De Vivo, Immaculata
    Giovannucci, Edward
    Kraft, Peter
    Huang, Jinyan
    Ma, Baoshan
    Ye, Yuanqing
    Chiu, Brian C. H.
    Liang, Liming
    Park, Ju-Hyun
    Chung, Charles C.
    Weisenburger, Dennis D.
    Fraumeni, Joseph F., Jr.
    Salles, Gilles
    Glenn, Martha
    Cannon-Albright, Lisa
    Curtin, Karen
    Wu, Xifeng
    Smedby, Karin E.
    de Sanjose, Silvia
    Skibola, Christine F.
    Berndt, Sonja I.
    Birmann, Brenda M.
    Chanock, Stephen J.
    Rothman, Nathaniel
    Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 8, p. 1663-1676Article in journal (Refereed)
    Abstract [en]

    Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82, P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51, P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

  • 32. Nead, Kevin T.
    et al.
    Li, Aihua
    Wehner, Mackenzie R.
    Neupane, Binod
    Gustafsson, Stefan
    Butterworth, Adam
    Engert, James C.
    Davis, A. Darlene
    Hegele, Robert A.
    Miller, Ruby
    den Hoed, Marcel
    Khaw, Kay-Tee
    Kilpelaeinen, Tuomas O.
    Wareham, Nick
    Edwards, Todd L.
    Hallmans, Goeran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Varga, Tibor V.
    Kardia, Sharon L. R.
    Smith, Jennifer A.
    Zhao, Wei
    Faul, Jessica D.
    Weir, David
    Mi, Jie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Xi, Bo
    Quinteros, Samuel Canizales
    Cooper, Cyrus
    Sayer, Avan Aihie
    Jameson, Karen
    Grontved, Anders
    Fornage, Myriam
    Sidney, Stephen
    Hanis, Craig L.
    Highland, Heather M.
    Haering, Hans-Ulrich
    Heni, Martin
    Lasky-Su, Jessica
    Weiss, Scott T.
    Gerhard, Glenn S.
    Still, Christopher
    Melka, Melkaey M.
    Pausova, Zdenka
    Paus, Tomas
    Grant, Struan F. A.
    Hakonarson, Hakon
    Price, R. Arlen
    Wang, Kai
    Scherag, Andre
    Hebebrand, Johannes
    Hinney, Anke
    Franks, Paul W.
    Frayling, Timothy M.
    McCarthy, Mark I.
    Hirschhorn, Joel N.
    Loos, Ruth J.
    Ingelsson, Erik
    Gerstein, Hertzel C.
    Yusuf, Salim
    Beyene, Joseph
    Anand, Sonia S.
    Meyre, David
    Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 12, p. 3582-3594Article in journal (Refereed)
    Abstract [en]

    Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) a parts per thousand yen 40 kg/m(2)], but their contribution to common obesity (BMI a parts per thousand yen 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 x 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 x 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (beta = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (beta = 0.02, 95% CI 0.00-0.03; P = 5.57 x 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

  • 33. Nettleton, Jennifer A
    et al.
    Follis, Jack L
    Ngwa, Julius S
    Smith, Caren E
    Ahmad, Shafqat
    Tanaka, Toshiko
    Wojczynski, Mary K
    Voortman, Trudy
    Lemaitre, Rozenn N
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Houston, Denise K
    Perälä, Mia-Maria
    Qi, Qibin
    Sonestedt, Emily
    Manichaikul, Ani
    Kanoni, Stavroula
    Ganna, Andrea
    Mikkilä, Vera
    North, Kari E
    Siscovick, David S
    Harald, Kennet
    Mckeown, Nicola M
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rissanen, Harri
    Liu, Yongmei
    Lahti, Jari
    Hu, Frank B
    Bandinelli, Stefania
    Rukh, Gull
    Rich, Stephen
    Booij, Lisanne
    Dmitriou, Maria
    Ax, Erika
    Raitakari, Olli
    Mukamal, Kenneth
    Männistö, Satu
    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.
    Jula, Antti
    Ericson, Ulrika
    Jacobs, David R, Jr
    Van Rooij, Frank J A
    Deloukas, Panos
    Sjögren, Per
    Kähönen, Mika
    Djousse, Luc
    Perola, Markus
    Barroso, Inês
    Hofman, Albert
    Stirrups, Kathleen
    Viikari, Jorma
    Uitterlinden, André G
    Kalafati, Ioanna P
    Franco, Oscar H.
    Mozaffarian, Dariush
    Salomaa, Veikko
    Borecki, Ingrid B
    Knekt, Paul
    Kritchevsky, Stephen B
    Eriksson, Johan G
    Dedoussis, George V
    Qi, Lu
    Ferrucci, Luigi
    Orho-Melander, Marju
    Zillikens, M Carola
    Ingelsson, Erik
    Lehtimäki, Terho
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden.
    Cupples, L Adrienne
    Loos, Ruth J F
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden; Department of Nutrition, Harvard Chan School of Public Health, Boston, MA, USA.
    Gene x dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 16, p. 4728-4738Article in journal (Refereed)
    Abstract [en]

    Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

  • 34.
    Nordin, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Akimoto, Chizuru
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Division of Neurology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji Shimotsukeshi, Tochigi 329-0498, Japan.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Alstermark, Helena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 11, p. 3133-3142Article in journal (Refereed)
    Abstract [en]

    A GGGGCC-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasians. However, little is known about the variability of the GGGGCC expansion in different tissues and whether this correlates with the observed phenotype. Here, we used Southern blotting to estimate the size of hexanucleotide expansions in C9orf72 in neural and non-neural tissues from 18 autopsied ALS and FTD patients with repeat expansion in blood. Digitalization of the Southern blot images allowed comparison of repeat number, smear distribution and expansion band intensity between tissues and between patients. We found marked intra-individual variation of repeat number between tissues, whereas there was less variation within each tissue group. In two patients, the size variation between tissues was extreme, with repeat numbers below 100 in all studied non-neural tissues, whereas expansions in neural tissues were 20-40 times greater and in the same size range observed in neural tissues of the other 16 patients. The expansion pattern in different tissues could not distinguish between diagnostic groups and no correlation was found between expansion size in frontal lobe and occurrence of cognitive impairment. In ALS patients, a less number of repeats in the cerebellum and parietal lobe correlated with earlier age of onset and a larger number of repeats in the parietal lobe correlated with a more rapid progression. In 43 other individuals without repeat expansion in blood, we find that repeat sizes up to 15 are stable, as no size variation between blood, brain and spinal cord was found.

  • 35. Ohta, Yasuyuki
    et al.
    Soucy, Genevieve
    Phaneuf, Daniel
    Audet, Jean-Nicolas
    Gros-Louis, Francois
    Rouleau, Guy A.
    Blasco, Helene
    Corcia, Philippe
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Univ Ulm, Dept Neurol, Ulm, Germany.
    Nordin, Frida
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Yamashita, Toru
    Abe, Koji
    Julien, Jean-Pierre
    Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 21, p. 4771-4786Article in journal (Refereed)
    Abstract [en]

    Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHG(BP413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413)L and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G37R) mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGB(P413L) allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGB(L413) allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.

  • 36.
    Olsson, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect2008In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, no 11, p. 1666-1672Article in journal (Refereed)
    Abstract [en]

    We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene-ISCU-specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.

  • 37. Piston, Dominik
    et al.
    Alvarez-Erviti, Lydia
    Bansal, Vikas
    Gargano, Daniela
    Yao, Zhi
    Szabadkai, Gyorgy
    Odell, Mark
    Puno, M. Rhyan
    Björkblom, Benny
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Maple-Grodem, Jodi
    Breuer, Peter
    Kaut, Oliver
    Larsen, Jan Petter
    Bonn, Stefan
    Moller, Simon Geir
    Wuellner, Ullrich
    Schapira, Anthony H. V.
    Gegg, Matthew E.
    DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 20, p. 4028-4041Article in journal (Refereed)
    Abstract [en]

    DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson's disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease.

  • 38. Prudencio, Mercedes
    et al.
    Hart, P John
    Borchelt, David R
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 17, p. 3217-3226Article in journal (Refereed)
    Abstract [en]

    To date, 146 different mutations in superoxide dismutase 1 (SOD1) have been identified in patients with familial amyotrophic lateral sclerosis (ALS). The mean age of disease onset in patients inheriting mutations in SOD1 is 45-47 years of age. However, although the length of disease duration is highly variable, there are examples of consistent disease durations associated with specific mutations (e. g. A4V, less than 2 years). In the present study, we have used a large set of data from SOD1-associated ALS pedigrees to identify correlations between disease features and biochemical/biophysical properties of more than 30 different variants of mutant SOD1. Using a reliable cell culture assay, we show that all ALS-associated mutations in SOD1 increase the inherent aggregation propensity of the protein. However, the relative propensity to do so varied considerably among mutants. We were not able to explain the variation in aggregation rates by differences in known protein properties such as enzyme activity, protein thermostability, mutation position or degree of change in protein charge. Similarly, we were not able to explain variability in the duration of disease in SOD1-associated ALS pedigrees by these properties. However, we find that the majority of pedigrees in which patients exhibit reproducibly short disease durations are associated with mutations that show a high inherent propensity to induce aggregation of SOD1.

  • 39.
    Qi, Qibin
    et al.
    Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10467 USA.
    Kilpeläinen, Tuomas O
    Downer, Mary K
    Tanaka, Toshiko
    Smith, Caren E
    Sluijs, Ivonne
    Sonestedt, Emily
    Chu, Audrey Y
    Renström, Frida
    Lin, Xiaochen
    Angquist, Lars H
    Huang, Jinyan
    Liu, Zhonghua
    Li, Yanping
    Asif Ali, Muhammad
    Xu, Min
    Ahluwalia, Tarunveer Singh
    Boer, Jolanda M A
    Chen, Peng
    Daimon, Makoto
    Eriksson, Johan
    Perola, Markus
    Friedlander, Yechiel
    Gao, Yu-Tang
    Heppe, Denise H M
    Holloway, John W
    Houston, Denise K
    Kanoni, Stavroula
    Kim, Yu-Mi
    Laaksonen, Maarit A
    Jääskeläinen, Tiina
    Lee, Nanette R
    Lehtimäki, Terho
    Lemaitre, Rozenn N
    Lu, Wei
    Luben, Robert N
    Manichaikul, Ani
    Männistö, Satu
    Marques-Vidal, Pedro
    Monda, Keri L
    Ngwa, Julius S
    Perusse, Louis
    van Rooij, Frank J A
    Xiang, Yong-Bing
    Wen, Wanqing
    Wojczynski, Mary K
    Zhu, Jingwen
    Borecki, Ingrid B
    Bouchard, Claude
    Cai, Qiuyin
    Cooper, Cyrus
    Dedoussis, George V
    Deloukas, Panos
    Ferrucci, Luigi
    Forouhi, Nita G
    Hansen, Torben
    Christiansen, Lene
    Hofman, Albert
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Jørgensen, Torben
    Karasawa, Shigeru
    Khaw, Kay-Tee
    Kim, Mi-Kyung
    Kristiansson, Kati
    Li, Huaixing
    Lin, Xu
    Liu, Yongmei
    Lohman, Kurt K
    Long, Jirong
    Mikkilä, Vera
    Mozaffarian, Dariush
    North, Kari
    Pedersen, Oluf
    Raitakari, Olli
    Rissanen, Harri
    Tuomilehto, Jaakko
    van der Schouw, Yvonne T
    Uitterlinden, André G
    Carola Zillikens, M
    Franco, Oscar H
    Shyong Tai, E
    Ou Shu, Xiao
    Siscovick, David S
    Toft, Ulla
    Monique Verschuren, W M
    Vollenweider, Peter
    Wareham, Nicholas J
    Witteman, Jacqueline C M
    Zheng, Wei
    Ridker, Paul M
    Kang, Jae H
    Liang, Liming
    Jensen, Majken K
    Curhan, Gary C
    Pasquale, Louis R
    Hunter, David J
    Mohlke, Karen L
    Uusitupa, Matti
    Adrienne Cupples, L
    Rankinen, Tuomo
    Orho-Melander, Marju
    Wang, Tao
    Chasman, Daniel I
    Franks, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA; Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA; Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.
    Sørensen, Thorkild I A
    Hu, Frank B
    Loos, Ruth J F
    Nettleton, Jennifer A
    Qi, Lu
    FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 25, p. 6961-6972Article in journal (Refereed)
    Abstract [en]

    FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

  • 40. Rahmioglu, Nilufer
    et al.
    Macgregor, Stuart
    Drong, Alexander W
    Hedman, Asa K
    Harris, Holly R
    Randall, Joshua C
    Prokopenko, Inga
    Nyholt, Dale R
    Morris, Andrew P
    Montgomery, Grant W
    Missmer, Stacey A
    Lindgren, Cecilia M
    Zondervan, Krina T
    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.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 4, p. 1185-1199Article in journal (Refereed)
    Abstract [en]

    Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.

  • 41.
    Renström, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Payne, Felicity
    Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Brito, Ema C
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Barroso, Ines
    Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Replication and extension of genome-wide association study results for obesity in 4,923 adults from Northern Sweden.2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 8, p. 1489-1496Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1, and PCSK1). Here we extend those studies by examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3,885 non-diabetic and 1,038 diabetic individuals with available measures of height, weight and BMI. Adipose mass and distribution was objectively assessed using dual energy X-ray absorptiometry (DEXA) in a sub-group of non-diabetics (n=2,206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P<0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752, and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the score were heavier (+2.6kg) and had more total (+2.4kg), gynoid (+191g), and abdominal (+136g) adipose tissue than those in the lowest quintile (all P<0.001). The genetic burden score significantly increased diabetes risk, with those in the highest quintile (n=193/594 cases/controls) being at 1.55-fold (95% CI: 1.21-1.99; P<0.0001) greater risk of type 2 diabetes than those in the lowest quintile (n=130/655 cases/controls). In summary, we have statistically replicated six of the previously associated obese-risk loci and our results suggest that the weight-inducing effects of these variants are explained largely by increased adipose accumulation.

  • 42. Sancho, Ana
    et al.
    Li, SiDe
    Paul, Thankam
    Zhang, Fan
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Vashisht, Ajay
    Balasubramaniyan, Natarajan
    Leleiko, Neal S
    Suchy, Frederick J
    Wohlschlegel, James A
    Zhang, Weijia
    Walsh, Martin J
    CHD6 regulates the topological arrangement of the CFTR locus2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 10, p. 2724-2732Article in journal (Refereed)
    Abstract [en]

    The control of transcription is regulated through the well-coordinated spatial and temporal interactions between distal genomic regulatory elements required for specialized cell-type and developmental gene expression programs. With recent findings CFTR has served as a model to understand the principles that govern genome-wide and topological organization of distal intra-chromosomal contacts as it relates to transcriptional control. This is due to the extensive characterization of the DNase hypersensitivity sites, modification of chromatin, transcription factor binding sites and the arrangement of these sites in CFTR consistent with the restrictive expression in epithelial cell types. Here, we identified CHD6 from a screen among several chromatin-remodeling proteins as a putative epigenetic modulator of CFTR expression. Moreover, our findings of CTCF interactions with CHD6 are consistent with the role described previously for CTCF in CFTR regulation. Our results now reveal that the CHD6 protein lies within the infrastructure of multiple transcriptional complexes, such as the FACT, PBAF, PAF1C, Mediator, SMC/Cohesion and MLL complexes. This model underlies the fundamental role CHD6 facilitates by tethering cis-acting regulatory elements of CFTR in proximity to these multi-subunit transcriptional protein complexes. Finally, we indicate that CHD6 structurally coordinates a three-dimensional stricture between intragenic elements of CFTR bound by several cell-type specific transcription factors, such as CDX2, SOX18, HNF4α and HNF1α. Therefore, our results reveal new insights into the epigenetic regulation of CFTR expression, whereas the manipulation of CFTR gene topology could be considered for treating specific indications of cystic fibrosis and/or pancreatitis.

  • 43. Schumacher, Fredrick R.
    et al.
    Berndt, Sonja I.
    Siddiq, Afshan
    Jacobs, Kevin B.
    Wang, Zhaoming
    Lindstrom, Sara
    Stevens, Victoria L.
    Chen, Constance
    Mondul, Alison M.
    Travis, Ruth C.
    Stram, Daniel O.
    Eeles, Rosalind A.
    Easton, Douglas F.
    Giles, Graham
    Hopper, John L.
    Neal, David E.
    Hamdy, Freddie C.
    Donovan, Jenny L.
    Muir, Kenneth
    Al Olama, Ali Amin
    Kote-Jarai, Zsofia
    Guy, Michelle
    Severi, Gianluca
    Gronberg, Henrik
    Isaacs, William B.
    Karlsson, Robert
    Wiklund, Fredrik
    Xu, Jianfeng
    Allen, Naomi E.
    Andriole, Gerald L.
    Barricarte, Aurelio
    Boeing, Heiner
    Bueno-de-Mesquita, H. Bas
    Crawford, E. David
    Diver, W. Ryan
    Gonzalez, Carlos A.
    Gaziano, J. Michael
    Giovannucci, Edward L.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    Le Marchand, Loic
    Ma, Jing
    Sieri, Sabina
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stampfer, Meir J.
    Tjonneland, Anne
    Vineis, Paolo
    Virtamo, Jarmo
    Vogel, Ulla
    Weinstein, Stephanie J.
    Yeager, Meredith
    Thun, Michael J.
    Kolonel, Laurence N.
    Henderson, Brian E.
    Albanes, Demetrius
    Hayes, Richard B.
    Feigelson, Heather Spencer
    Riboli, Elio
    Hunter, David J.
    Chanock, Stephen J.
    Haiman, Christopher A.
    Kraft, Peter
    Genome-wide association study identifies new prostate cancer susceptibility loci2011In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 19, p. 3867-3875Article in journal (Refereed)
    Abstract [en]

    Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade >= 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P = 4.3 x 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P = 8.6 x 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P = 0.72 and P = 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.

  • 44. Siddiq, Afshan
    et al.
    Couch, Fergus J.
    Chen, Gary K.
    Lindstrom, Sara
    Eccles, Diana
    Millikan, Robert C.
    Michailidou, Kyriaki
    Stram, Daniel O.
    Beckmann, Lars
    Rhie, Suhn Kyong
    Ambrosone, Christine B.
    Aittomaki, Kristiina
    Amiano, Pilar
    Apicella, Carmel
    Baglietto, Laura
    Bandera, Elisa V.
    Beckmann, Matthias W.
    Berg, Christine D.
    Bernstein, Leslie
    Blomqvist, Carl
    Brauch, Hiltrud
    Brinton, Louise
    Bui, Quang M.
    Buring, Julie E.
    Buys, Saundra S.
    Campa, Daniele
    Carpenter, Jane E.
    Chasman, Daniel I.
    Chang-Claude, Jenny
    Chen, Constance
    Clavel-Chapelon, Francoise
    Cox, Angela
    Cross, Simon S.
    Czene, Kamila
    Deming, Sandra L.
    Diasio, Robert B.
    Diver, W. Ryan
    Dunning, Alison M.
    Durcan, Lorraine
    Ekici, Arif B.
    Fasching, Peter A.
    Feigelson, Heather Spencer
    Fejerman, Laura
    Figueroa, Jonine D.
    Fletcher, Olivia
    Flesch-Janys, Dieter
    Gaudet, Mia M.
    Gerty, Susan M.
    Rodriguez-Gil, Jorge L.
    Giles, Graham G.
    van Gils, Carla H.
    Godwin, Andrew K.
    Graham, Nikki
    Greco, Dario
    Hall, Per
    Hankinson, Susan E.
    Hartmann, Arndt
    Hein, Rebecca
    Heinz, Judith
    Hoover, Robert N.
    Hopper, John L.
    Hu, Jennifer J.
    Huntsman, Scott
    Ingles, Sue A.
    Irwanto, Astrid
    Isaacs, Claudine
    Jacobs, Kevin B.
    John, Esther M.
    Justenhoven, Christina
    Kaaks, Rudolf
    Kolonel, Laurence N.
    Coetzee, Gerhard A.
    Lathrop, Mark
    Le Marchand, Loic
    Lee, Adam M.
    Lee, I-Min
    Lesnick, Timothy
    Lichtner, Peter
    Liu, Jianjun
    Lund, Eiliv
    Makalic, Enes
    Martin, Nicholas G.
    McLean, Catriona A.
    Meijers-Heijboer, Hanne
    Meindl, Alfons
    Miron, Penelope
    Monroe, Kristine R.
    Montgomery, Grant W.
    Mueller-Myhsok, Bertram
    Nickels, Stefan
    Nyante, Sarah J.
    Olswold, Curtis
    Overvad, Kim
    Palli, Domenico
    Park, Daniel J.
    Palmer, Julie R.
    Pathak, Harsh
    Peto, Julian
    Pharoah, Paul
    Rahman, Nazneen
    Rivadeneira, Fernando
    Schmidt, Daniel F.
    Schmutzler, Rita K.
    Slager, Susan
    Southey, Melissa C.
    Stevens, Kristen N.
    Sinn, Hans-Peter
    Press, Michael F.
    Ross, Eric
    Riboli, Elio
    Ridker, Paul M.
    Schumacher, Fredrick R.
    Severi, Gianluca
    Silva, Isabel dos Santos
    Stone, Jennifer
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tapper, William J.
    Thun, Michael J.
    Travis, Ruth C.
    Turnbull, Clare
    Uitterlinden, Andre G.
    Waisfisz, Quinten
    Wang, Xianshu
    Wang, Zhaoming
    Weaver, JoEllen
    Schulz-Wendtland, Ruediger
    Wilkens, Lynne R.
    Van Den Berg, David
    Zheng, Wei
    Ziegler, Regina G.
    Ziv, Elad
    Nevanlinna, Heli
    Easton, Douglas F.
    Hunter, David J.
    Henderson, Brian E.
    Chanock, Stephen J.
    Garcia-Closas, Montserrat
    Kraft, Peter
    Haiman, Christopher A.
    Vachon, Celine M.
    A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q112012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 24, p. 5373-5384Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P 1 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR 1.16; P 1.1 10(8)) but showed a weaker association with overall breast cancer (OR 1.08, P 1.3 10(6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR 1.01, P 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR 1.12; P 1.1 10(9)), and with both ER-positive (OR 1.09; P 1.5 10(5)) and ER-negative (OR 1.16, P 2.5 10(7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

  • 45. Synofzik, Matthis
    et al.
    Ronchi, Dario
    Keskin, Isil
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Basak, Ayse N.
    Wilhelm, Christian
    Gobbi, Claudio
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Biskup, Saskia
    Zecca, Chiara
    Fernandez-Santiago, Ruben
    Kaugesaar, Toomas
    Schoels, Ludger
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 16, p. 3568-3574Article in journal (Refereed)
    Abstract [en]

    A reason for screening amyotrophic lateral sclerosis (ALS) patients for mutations in the superoxide dismutase-1 (SOD1) gene is the opportunity to find novel mutations with properties that can give information on pathogenesis. A novel c.352CG (L117V) SOD1 mutation was found in two Syrian ALS families living in Europe. The disease showed unusually low penetrance and slow progression. In erythrocytes, the total SOD1 activity, as well as specific activity of the mutant protein, was equal in carriers of the mutation and family controls lacking SOD1 mutations. The structural stabilities of the L117V mutant and wild-type SOD1 under denaturing conditions were likewise equal, but considerably lower than that of murine SOD1. As analyzed with an ELISA specific for misfolded SOD1 species, no differences were found in the content of misfolded SOD1 protein between extracts of fibroblasts from wild-type controls and from an L117V patient. In contrast, elevated levels of misfolded SOD1 protein were found in fibroblasts from ALS patients carrying seven other mutations in the SOD1 gene. We conclude that mutations in SOD1 that result in a fully stable protein are associated with low disease penetrance for ALS and may be found in cases of apparently sporadic ALS. Wild-type human SOD1 is moderately stable, and was found here to be within the stability range of ALS-causing SOD1 variants, lending support to the hypothesis that wild-type SOD1 could be more generally involved in ALS pathogenesis.

  • 46. Wang, Zhaoming
    et al.
    Zhu, Bin
    Zhang, Mingfeng
    Parikh, Hemang
    Jia, Jinping
    Chung, Charles C
    Sampson, Joshua N
    Hoskins, Jason W
    Hutchinson, Amy
    Burdette, Laurie
    Ibrahim, Abdisamad
    Hautman, Christopher
    Raj, Preethi S
    Abnet, Christian C
    Adjei, Andrew A
    Ahlbom, Anders
    Albanes, Demetrius
    Allen, Naomi E
    Ambrosone, Christine B
    Aldrich, Melinda
    Amiano, Pilar
    Amos, Christopher
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andriole, Gerald
    Andrulis, Irene L
    Arici, Cecilia
    Arslan, Alan A
    Austin, Melissa A
    Baris, Dalsu
    Barkauskas, Donald A
    Bassig, Bryan A
    Beane Freeman, Laura E
    Berg, Christine D
    Berndt, Sonja I
    Bertazzi, Pier Alberto
    Biritwum, Richard B
    Black, Amanda
    Blot, William
    Boeing, Heiner
    Boffetta, Paolo
    Bolton, Kelly
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M
    Brennan, Paul
    Brinton, Louise A
    Brotzman, Michelle
    Bueno-de-Mesquita, H Bas
    Buring, Julie E
    Butler, Mary Ann
    Cai, Qiuyin
    Cancel-Tassin, Geraldine
    Canzian, Federico
    Cao, Guangwen
    Caporaso, Neil E
    Carrato, Alfredo
    Carreon, Tania
    Carta, Angela
    Chang, Gee-Chen
    Chang, I-Shou
    Chang-Claude, Jenny
    Che, Xu
    Chen, Chien-Jen
    Chen, Chih-Yi
    Chen, Chung-Hsing
    Chen, Constance
    Chen, Kuan-Yu
    Chen, Yuh-Min
    Chokkalingam, Anand P
    Chu, Lisa W
    Clavel-Chapelon, Francoise
    Colditz, Graham A
    Colt, Joanne S
    Conti, David
    Cook, Michael B
    Cortessis, Victoria K
    Crawford, E David
    Cussenot, Olivier
    Davis, Faith G
    De Vivo, Immaculata
    Deng, Xiang
    Ding, Ti
    Dinney, Colin P
    Di Stefano, Anna Luisa
    Diver, W Ryan
    Duell, Eric J
    Elena, Joanne W
    Fan, Jin-Hu
    Feigelson, Heather Spencer
    Feychting, Maria
    Figueroa, Jonine D
    Flanagan, Adrienne M
    Fraumeni, Joseph F
    Freedman, Neal D
    Fridley, Brooke L
    Fuchs, Charles S
    Gago-Dominguez, Manuela
    Gallinger, Steven
    Gao, Yu-Tang
    Gapstur, Susan M
    Garcia-Closas, Montserrat
    Garcia-Closas, Reina
    Gastier-Foster, Julie M
    Gaziano, J Michael
    Gerhard, Daniela S
    Giffen, Carol A
    Giles, Graham G
    Gillanders, Elizabeth M
    Giovannucci, Edward L
    Goggins, Michael
    Gokgoz, Nalan
    Goldstein, Alisa M
    Gonzalez, Carlos
    Gorlick, Richard
    Greene, Mark H
    Gross, Myron
    Grossman, H Barton
    Grubb, Robert
    Gu, Jian
    Guan, Peng
    Haiman, Christopher A
    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.
    Hankinson, Susan E
    Harris, Curtis C
    Hartge, Patricia
    Hattinger, Claudia
    Hayes, Richard B
    He, Qincheng
    Helman, Lee
    Henderson, Brian E
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoffman-Bolton, Judith
    Hohensee, Chancellor
    Holly, Elizabeth A
    Hong, Yun-Chul
    Hoover, Robert N
    Hosgood, H Dean
    Hsiao, Chin-Fu
    Hsing, Ann W
    Hsiung, Chao Agnes
    Hu, Nan
    Hu, Wei
    Hu, Zhibin
    Huang, Ming-Shyan
    Hunter, David J
    Inskip, Peter D
    Ito, Hidemi
    Jacobs, Eric J
    Jacobs, Kevin B
    Jenab, Mazda
    Ji, Bu-Tian
    Johansen, Christoffer
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johnson, Alison
    Kaaks, Rudolf
    Kamat, Ashish M
    Kamineni, Aruna
    Karagas, Margaret
    Khanna, Chand
    Khaw, Kay-Tee
    Kim, Christopher
    Kim, In-Sam
    Kim, Jin Hee
    Kim, Yeul Hong
    Kim, Young-Chul
    Kim, Young Tae
    Kang, Chang Hyun
    Jung, Yoo Jin
    Kitahara, Cari M
    Klein, Alison P
    Klein, Robert
    Kogevinas, Manolis
    Koh, Woon-Puay
    Kohno, Takashi
    Kolonel, Laurence N
    Kooperberg, Charles
    Kratz, Christian P
    Krogh, Vittorio
    Kunitoh, Hideo
    Kurtz, Robert C
    Kurucu, Nilgun
    Lan, Qing
    Lathrop, Mark
    Lau, Ching C
    Lecanda, Fernando
    Lee, Kyoung-Mu
    Lee, Maxwell P
    Le Marchand, Loic
    Lerner, Seth P
    Li, Donghui
    Liao, Linda M
    Lim, Wei-Yen
    Lin, Dongxin
    Lin, Jie
    Lindstrom, Sara
    Linet, Martha S
    Lissowska, Jolanta
    Liu, Jianjun
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lloreta, Josep
    Lu, Daru
    Ma, Jing
    Malats, Nuria
    Mannisto, Satu
    Marina, Neyssa
    Mastrangelo, Giuseppe
    Matsuo, Keitaro
    McGlynn, Katherine A
    McKean-Cowdin, Roberta
    McNeill, Lorna H
    McWilliams, Robert R
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Meltzer, Paul S
    Mensah, James E
    Miao, Xiaoping
    Michaud, Dominique S
    Mondul, Alison M
    Moore, Lee E
    Muir, Kenneth
    Niwa, Shelley
    Olson, Sara H
    Orr, Nick
    Panico, Salvatore
    Park, Jae Yong
    Patel, Alpa V
    Patino-Garcia, Ana
    Pavanello, Sofia
    Peeters, Petra H M
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M
    Picci, Piero
    Pike, Malcolm C
    Porru, Stefano
    Prescott, Jennifer
    Pu, Xia
    Purdue, Mark P
    Qiao, You-Lin
    Rajaraman, Preetha
    Riboli, Elio
    Risch, Harvey A
    Rodabough, Rebecca J
    Rothman, Nathaniel
    Ruder, Avima M
    Ryu, Jeong-Seon
    Sanson, Marc
    Schned, Alan
    Schumacher, Fredrick R
    Schwartz, Ann G
    Schwartz, Kendra L
    Schwenn, Molly
    Scotlandi, Katia
    Seow, Adeline
    Serra, Consol
    Serra, Massimo
    Sesso, Howard D
    Severi, Gianluca
    Shen, Hongbing
    Shen, Min
    Shete, Sanjay
    Shiraishi, Kouya
    Shu, Xiao-Ou
    Siddiq, Afshan
    Sierrasesumaga, Luis
    Sierri, Sabina
    Loon Sihoe, Alan Dart
    Silverman, Debra T
    Simon, Matthias
    Southey, Melissa C
    Spector, Logan
    Spitz, Margaret
    Stampfer, Meir
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stern, Mariana C
    Stevens, Victoria L
    Stolzenberg-Solomon, Rachael Z
    Stram, Daniel O
    Strom, Sara S
    Su, Wu-Chou
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sung, Sook Whan
    Swerdlow, Anthony
    Tan, Wen
    Tanaka, Hideo
    Tang, Wei
    Tang, Ze-Zhang
    Tardon, Adonina
    Tay, Evelyn
    Taylor, Philip R
    Tettey, Yao
    Thomas, David M
    Tirabosco, Roberto
    Tjonneland, Anne
    Tobias, Geoffrey S
    Toro, Jorge R
    Travis, Ruth C
    Trichopoulos, Dimitrios
    Troisi, Rebecca
    Truelove, Ann
    Tsai, Ying-Huang
    Tucker, Margaret A
    Tumino, Rosario
    Van Den Berg, David
    Van Den Eeden, Stephen K
    Vermeulen, Roel
    Vineis, Paolo
    Visvanathan, Kala
    Vogel, Ulla
    Wang, Chaoyu
    Wang, Chengfeng
    Wang, Junwen
    Wang, Sophia S
    Weiderpass, Elisabete
    Weinstein, Stephanie J
    Wentzensen, Nicolas
    Wheeler, William
    White, Emily
    Wiencke, John K
    Wolk, Alicja
    Wolpin, Brian M
    Wong, Maria Pik
    Wrensch, Margaret
    Wu, Chen
    Wu, Tangchun
    Wu, Xifeng
    Wu, Yi-Long
    Wunder, Jay S
    Xiang, Yong-Bing
    Xu, Jun
    Yang, Hannah P
    Yang, Pan-Chyr
    Yatabe, Yasushi
    Ye, Yuanqing
    Yeboah, Edward D
    Yin, Zhihua
    Ying, Chen
    Yu, Chong-Jen
    Yu, Kai
    Yuan, Jian-Min
    Zanetti, Krista A
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Zhou, Baosen
    Mirabello, Lisa
    Savage, Sharon A
    Kraft, Peter
    Chanock, Stephen J
    Yeager, Meredith
    Landi, Maria Terese
    Shi, Jianxin
    Chatterjee, Nilanjan
    Amundadottir, Laufey T
    Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.332014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 24, p. 6616-6633Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

  • 47. Wu, Xifeng
    et al.
    Scelo, Ghislaine
    Purdue, Mark P.
    Rothman, Nathaniel
    Johansson, Mattias
    International Agency for Research on Cancer (IARC), Lyon, France.
    Ye, Yuanqing
    Wang, Zhaoming
    Zelenika, Diana
    Moore, Lee E.
    Wood, Christopher G.
    Prokhortchouk, Egor
    Gaborieau, Valerie
    Jacobs, Kevin B.
    Chow, Wong-Ho
    Toro, Jorge R.
    Zaridze, David
    Lin, Jie
    Lubinski, Jan
    Trubicka, Joanna
    Szeszenia-Dabrowska, Neonilia
    Lissowska, Jolanta
    Rudnai, Peter
    Fabianova, Eleonora
    Mates, Dana
    Jinga, Viorel
    Bencko, Vladimir
    Slamova, Alena
    Holcatova, Ivana
    Navratilova, Marie
    Janout, Vladimir
    Boffetta, Paolo
    Colt, Joanne S.
    Davis, Faith G.
    Schwartz, Kendra L.
    Banks, Rosamonde E.
    Selby, Peter J.
    Harnden, Patricia
    Berg, Christine D.
    Hsing, Ann W.
    Grubb, Robert L., III
    Boeing, Heiner
    Vineis, Paolo
    Clavel-Chapelon, Francoise
    Palli, Domenico
    Tumino, Rosario
    Krogh, Vittorio
    Panico, Salvatore
    Duell, Eric J.
    Ramon Quiros, Jose
    Sanchez, Maria-Jose
    Navarro, Carmen
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Allen, Naomi E.
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H. M.
    Trichopoulos, Dimitrios
    Linseisen, Jakob
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Overvad, Kim
    Tjonneland, Anne
    Romieu, Isabelle
    Riboli, Elio
    Stevens, Victoria L.
    Thun, Michael J.
    Diver, W. Ryan
    Gapstur, Susan M.
    Pharoah, Paul D.
    Easton, Douglas F.
    Albanes, Demetrius
    Virtamo, Jarmo
    Vatten, Lars
    Hveem, Kristian
    Fletcher, Tony
    Koppova, Kvetoslava
    Cussenot, Olivier
    Cancel-Tassin, Geraldine
    Benhamou, Simone
    Hildebrandt, Michelle A.
    Pu, Xia
    Foglio, Mario
    Lechner, Doris
    Hutchinson, Amy
    Yeager, Meredith
    Fraumeni, Joseph F., Jr.
    Lathrop, Mark
    Skryabin, Konstantin G.
    McKay, James D.
    Gu, Jian
    Brennan, Paul
    Chanock, Stephen J.
    A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.232012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 2, p. 456-462Article in journal (Refereed)
    Abstract [en]

    Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome- wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 x 10(-10) and P = 6.07 x 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.

1 - 47 of 47
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