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  • 1. Abel, Olubunmi
    et al.
    Powell, John F.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Al-Chalabi, Ammar
    ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics2012In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, no 9, p. 1345-1351Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is the commonest adult onset motor neuron disease, with a peak age of onset in the seventh decade. With advances in genetic technology, there is an enormous increase in the volume of genetic data produced, and a corresponding need for storage, analysis, and interpretation, particularly as our understanding of the relationships between genotype and phenotype mature. Here, we present a system to enable this in the form of the ALS Online Database (ALSoD at http://alsod.iop.kcl.ac.uk), a freely available database that has been transformed from a single gene storage facility recording mutations in the SOD1 gene to a multigene ALS bioinformatics repository and analytical instrument combining genotype, phenotype, and geographical information with associated analysis tools. These include a comparison tool to evaluate genes side by side or jointly with user configurable features, a pathogenicity prediction tool using a combination of computational approaches to distinguish variants with nonfunctional characteristics from disease-associated mutations with more dangerous consequences, and a credibility tool to enable ALS researchers to objectively assess the evidence for gene causation in ALS. Furthermore, integration of external tools, systems for feedback, annotation by users, and two-way links to collaborators hosting complementary databases further enhance the functionality of ALSoD. Hum Mutat 33:1345-1351, 2012. (c) 2012 Wiley Periodicals, Inc.

  • 2. Adams, Hieab H. H.
    et al.
    Hibar, Derrek P.
    Chouraki, Vincent
    Stein, Jason L.
    Nyquist, Paul A.
    Renteria, Miguel E.
    Trompet, Stella
    Arias-Vasquez, Alejandro
    Seshadri, Sudha
    Desrivieres, Sylvane
    Beecham, Ashley H.
    Jahanshad, Neda
    Wittfeld, Katharine
    Van der Lee, Sven J.
    Abramovic, Lucija
    Alhusaini, Saud
    Amin, Najaf
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Arfanakis, Konstantinos
    Aribisala, Benjamin S.
    Armstrong, Nicola J.
    Athanasiu, Lavinia
    Axelsson, Tomas
    Beiser, Alexa
    Bernard, Manon
    Bis, Joshua C.
    Blanken, Laura M. E.
    Blanton, Susan H.
    Bohlken, Marc M.
    Boks, Marco P.
    Bralten, Janita
    Brickman, Adam M.
    Carmichael, Owen
    Chakravarty, M. Mallar
    Chauhan, Ganesh
    Chen, Qiang
    Ching, Christopher R. K.
    Cuellar-Partida, Gabriel
    Den Braber, Anouk
    Doan, Nhat Trung
    Ehrlich, Stefan
    Filippi, Irina
    Ge, Tian
    Giddaluru, Sudheer
    Goldman, Aaron L.
    Gottesman, Rebecca F.
    Greven, Corina U.
    Grimm, Oliver
    Griswold, Michael E.
    Guadalupe, Tulio
    Hass, Johanna
    Haukvik, Unn K.
    Hilal, Saima
    Hofer, Edith
    Hoehn, David
    Holmes, Avram J.
    Hoogman, Martine
    Janowitz, Deborah
    Jia, Tianye
    Kasperaviciute, Dalia
    Kim, Sungeun
    Klein, Marieke
    Kraemer, Bernd
    Lee, Phil H.
    Liao, Jiemin
    Liewald, David C. M.
    Lopez, Lorna M.
    Luciano, Michelle
    Macare, Christine
    Marquand, Andre
    Matarin, Mar
    Mather, Karen A.
    Mattheisen, Manuel
    Mazoyer, Bernard
    Mckay, David R.
    McWhirter, Rebekah
    Milaneschi, Yuri
    Mirza-Schreiber, Nazanin
    Muetzel, Ryan L.
    Maniega, Susana Munoz
    Nho, Kwangsik
    Nugent, Allison C.
    Loohuis, Loes M. Olde
    Oosterlaan, Jaap
    Papmeyer, Martina
    Pappa, Irene
    Pirpamer, Lukas
    Pudas, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Puetz, Benno
    Rajan, Kumar B.
    Ramasamy, Adaikalavan
    Richards, Jennifer S.
    Risacher, Shannon L.
    Roiz-Santianez, Roberto
    Rommelse, Nanda
    Rose, Emma J.
    Royle, Natalie A.
    Rundek, Tatjana
    Saemann, Philipp G.
    Satizabal, Claudia L.
    Schmaal, Lianne
    Schork, Andrew J.
    Shen, Li
    Shin, Jean
    Shumskaya, Elena
    Smith, Albert V.
    Sprooten, Emma
    Strike, Lachlan T.
    Teumer, Alexander
    Thomson, Russell
    Tordesillas-Gutierrez, Diana
    Toro, Roberto
    Trabzuni, Daniah
    Vaidya, Dhananjay
    Van der Grond, Jeroen
    Van der Meer, Dennis
    Van Donkelaar, Marjolein M. J.
    Van Eijk, Kristel R.
    Van Erp, Theo G. M.
    Van Rooij, Daan
    Walton, Esther
    Westlye, Lars T.
    Whelan, Christopher D.
    Windham, Beverly G.
    Winkler, Anderson M.
    Woldehawariat, Girma
    Wolf, Christiane
    Wolfers, Thomas
    Xu, Bing
    Yanek, Lisa R.
    Yang, Jingyun
    Zijdenbos, Alex
    Zwiers, Marcel P.
    Agartz, Ingrid
    Aggarwal, Neelum T.
    Almasy, Laura
    Ames, David
    Amouyel, Philippe
    Andreassen, Ole A.
    Arepalli, Sampath
    Assareh, Amelia A.
    Barral, Sandra
    Bastin, Mark E.
    Becker, Diane M.
    Becker, James T.
    Bennett, David A.
    Blangero, John
    van Bokhoven, Hans
    Boomsma, Dorret I.
    Brodaty, Henry
    Brouwer, Rachel M.
    Brunner, Han G.
    Buckner, Randy L.
    Buitelaar, Jan K.
    Bulayeva, Kazima B.
    Cahn, Wiepke
    Calhoun, Vince D.
    Cannon, Dara M.
    Cavalleri, Gianpiero L.
    Chen, Christopher
    Cheng, Ching -Yu
    Cichon, Sven
    Cookson, Mark R.
    Corvin, Aiden
    Crespo-Facorro, Benedicto
    Curran, Joanne E.
    Czisch, Michael
    Dale, Anders M.
    Davies, Gareth E.
    De Geus, Eco J. C.
    De Jager, Philip L.
    de Zubicaray, Greig I.
    Delanty, Norman
    Depondt, Chantal
    DeStefano, Anita L.
    Dillman, Allissa
    Djurovic, Srdjan
    Donohoe, Gary
    Drevets, Wayne C.
    Duggirala, Ravi
    Dyer, Thomas D.
    Erk, Susanne
    Espeseth, Thomas
    Evans, Denis A.
    Fedko, Iryna
    Fernandez, Guillen
    Ferrucci, Luigi
    Fisher, Simon E.
    Fleischman, Debra A.
    Ford, Ian
    Foroud, Tatiana M.
    Fox, Peter T.
    Francks, Clyde
    Fukunaga, Masaki
    Gibbs, J. Raphael
    Glahn, David C.
    Gollub, Randy L.
    Goring, Harald H. H.
    Grabe, Hans J.
    Green, Robert C.
    Gruber, Oliver
    Gudnason, Vilmundur
    Guelfi, Sebastian
    Hansell, Narelle K.
    Hardy, John
    Hartman, Catharina A.
    Hashimoto, Ryota
    Hegenscheid, Katrin
    Heinz, Andreas
    Le Hellard, Stephanie
    Hernandez, Dena G.
    Heslenfeld, Dirk J.
    Ho, Beng-Choon
    Hoekstra, Pieter J.
    Hoffmann, Wolfgang
    Hofman, Albert
    Holsboer, Florian
    Homuth, Georg
    Hosten, Norbert
    Hottenga, Jouke-Jan
    Pol, Hilleke E. Hulshoff
    Ikeda, Masashi
    Ikram, M. Kamran
    Jack, Clifford R., Jr.
    Jenldnson, Mark
    Johnson, Robert
    Jonsson, Erik G.
    Jukema, J. Wouter
    Kahn, Rene S.
    Kanai, Ryota
    Kloszewska, Iwona
    Knopman, David S.
    Kochunov, Peter
    Kwok, John B.
    Lawrie, Stephen M.
    Lemaitre, Herve
    Liu, Xinmin
    Longo, Dan L.
    Longstreth, W. T., Jr.
    Lopez, Oscar L.
    Lovestone, Simon
    Martinez, Oliver
    Martinot, Jean-Luc
    Mattay, Venkata S.
    McDonald, Colm
    McIntosh, Andrew M.
    McMahon, Katie L.
    McMahon, Francis J.
    Mecocci, Patrizia
    Melle, Ingrid
    Meyer-Lindenberg, Andreas
    Mohnke, Sebastian
    Montgomery, Grant W.
    Morris, Derek W.
    Mosley, Thomas H.
    Muhleisen, Thomas W.
    Mueller-Myhsok, Bertram
    Nalls, Michael A.
    Nauck, Matthias
    Nichols, Thomas E.
    Niessen, Wiro J.
    Noethen, Markus M.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ohi, Kazutaka
    Olvera, Rene L.
    Ophoff, Roel A.
    Pandolfo, Massimo
    Paus, Tomas
    Pausova, Zdenka
    Penninx, Brenda W. J. H.
    Pike, G. Bruce
    Potkin, Steven G.
    Psaty, Bruce M.
    Reppermund, Simone
    Rietschel, Marcella
    Roffman, Joshua L.
    Romanczuk-Seiferth, Nina
    Rotter, Jerome I.
    Ryten, Mina
    Sacco, Ralph L.
    Sachdev, Perminder S.
    Saykin, Andrew J.
    Schmidt, Reinhold
    Schofield, Peter R.
    Sigurdsson, Sigurdur
    Simmons, Andy
    Singleton, Andrew
    Sisodiya, Sanjay M.
    Smith, Colin
    Smoller, Jordan W.
    Soininen, Hindu.
    Srikanth, Velandai
    Steen, Vidar M.
    Stott, David J.
    Sussmann, Jessika E.
    Thalamuthu, Anbupalam
    Tiemeier, Henning
    Toga, Arthur W.
    Traynor, Bryan J.
    Troncoso, Juan
    Turner, Jessica A.
    Tzourio, Christophe
    Uitterlinden, Andre G.
    Hernandez, Maria C. Valdes
    Van der Brug, Marcel
    Van der Lugt, Aad
    Van der Wee, Nic J. A.
    Van Duijn, Cornelia M.
    Van Haren, Neeltje E. M.
    Van't Ent, Dennis
    Van Tol, Marie Jose
    Vardarajan, Badri N.
    Veltman, Dick J.
    Vernooij, Meike W.
    Voelzke, Henry
    Walter, Henrik
    Wardlaw, Joanna M.
    Wassink, Thomas H.
    Weale, Michael E.
    Weinberger, Daniel R.
    Weiner, Michael W.
    Wen, Wei
    Westman, Eric
    White, Tonya
    Wong, Tien Y.
    Wright, Clinton B.
    Zielke, H. Ronald
    Zonderman, Alan B.
    Deary, Ian J.
    DeCarli, Charles
    Schmidt, Helena
    Martin, Nicholas G.
    De Craen, Anton J. M.
    Wright, Margaret J.
    Launer, Lenore J.
    Schumann, Gunter
    Fornage, Myriam
    Franke, Barbara
    Debette, Stephanie
    Medland, Sarah E.
    Ikram, M. Arfan
    Thompson, Paul M.
    Novel genetic loci underlying human intracranial volume identified through genome-wide association2016In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 19, no 12, p. 1569-1582Article in journal (Refereed)
    Abstract [en]

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

  • 3. Ahmad, Shafqat
    et al.
    Mora, Samia
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
    Orho-Melander, Marju
    Ridker, Paul M.
    Hu, Frank B.
    Chasman, Daniel I.
    Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 231-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.

    METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.

    RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.

    CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

  • 4. Ahmad, Shafqat
    et al.
    Mora, Samia
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
    Orho-Melander, Marju
    Ridker, Paul M.
    Hu, Frank B.
    Chasman, Daniel I.
    Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 231-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.

    METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.

    RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.

    CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

  • 5. Ahmad, Shafqat
    et al.
    Mora, Samia
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
    Orho-Melander, Marju
    Ridker, Paul M.
    Hu, Frank B.
    Chasman, Daniel I.
    Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study2018In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 231-241Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.

    METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.

    RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.

    CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

  • 6. Ahmad, Shafqat
    et al.
    Rukh, Gull
    Varga, Tibor V
    Ali, Ashfaq
    Kurbasic, Azra
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology. Lund University.
    Ericson, Ulrika
    Koivula, Robert W
    Chu, Audrey Y
    Rose, Lynda M
    Ganna, Andrea
    Qi, Qibin
    Stancakova, Alena
    Sandholt, Camilla H
    Elks, Cathy E
    Curhan, Gary
    Jensen, Majken K
    Tamimi, Rulla M
    Allin, Kristine H
    Jorgensen, Torben
    Brage, Soren
    Langenberg, Claudia
    Aadahl, Mette
    Grarup, Niels
    Linneberg, Allan
    Pare, Guillaume
    Magnusson, Patrik KE
    Pedersen, Nancy L
    Boehnke, Michael
    Hamsten, Anders
    Mohlke, Karen L
    Pasquale, Louis T
    Pedersen, Oluf
    Scott, Robert A
    Ridker, Paul M
    Ingelsson, Erik
    Laakso, Markku
    Hansen, Torben
    Qi, Lu
    Wareham, Nicholas J
    Chasman, Daniel I
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hu, Frank B
    Renström, Frida
    Orho-Melander, Marju
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lund University and Harvard University.
    Gene x physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 7, p. e1003607-Article in journal (Refereed)
    Abstract [en]

    Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS x physical activity interaction effect estimate (P-interaction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, P-interaction = 0.014 vs. n = 71,611, P-interaction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (P-interaction = 0.003) and the SEC16B rs10913469 (P-interaction = 0.025) variants showed evidence of SNP x physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

  • 7. Ahmad, Shafqat
    et al.
    Varga, Tibor V
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gene x environment interactions in obesity: the state of the evidence2013In: Human Heredity, ISSN 0001-5652, E-ISSN 1423-0062, Vol. 75, no 2-4, p. 106-115Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Obesity is a pervasive and highly prevalent disease that poses substantial health risks to those it affects. The rapid emergence of obesity as a global epidemic and the patterns and distributions of the condition within and between populations suggest that interactions between inherited biological factors (e.g. genes) and relevant environmental factors (e.g. diet and physical activity) may underlie the current obesity epidemic.

    Methods: We discuss the rationale for the assertion that gene x lifestyle interactions cause obesity, systematically appraise relevant literature, and consider knowledge gaps future studies might seek to bridge. Results: We identified >200 relevant studies, of which most are relatively small scale and few provide replication data.

    Conclusion: Although studies on gene x lifestyle interactions in obesity point toward the presence of such interactions, improved data standardization, appropriate pooling of data and resources, innovative study designs, and the application of powerful statistical methods will be required if translatable examples of gene x lifestyle interactions in obesity are to be identified. Future studies, of which most will be observational, should ideally be accompanied by appropriate replication data and, where possible, by analogous findings from experimental settings where clinically relevant traits (e.g. weight regain and weight cycling) are outcomes.

    (C) 2013 S. Karger AG, Basel

  • 8.
    Akimoto, Chizuru
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Volk, Alexander E.
    van Blitterswijk, Marka
    Van den Broeck, Marleen
    Leblond, Claire S.
    Lumbroso, Serge
    Camu, William
    Neitzel, Birgit
    Onodera, Osamu
    van Rheenen, Wouter
    Pinto, Susana
    Weber, Markus
    Smith, Bradley
    Proven, Melanie
    Talbot, Kevin
    Keagle, Pamela
    Chesi, Alessandra
    Ratti, Antonia
    van der Zee, Julie
    Alstermark, Helena
    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.
    Calini, Daniela
    Nordin, Angelica
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Tradowsky, Daniela C.
    Just, Walter
    Daoud, Hussein
    Angerbauer, Sabrina
    DeJesus-Hernandez, Mariely
    Konno, Takuya
    Lloyd-Jani, Anjali
    de Carvalho, Mamede
    Mouzat, Kevin
    Landers, John E.
    Veldink, Jan H.
    Silani, Vincenzo
    Gitler, Aaron D.
    Shaw, Christopher E.
    Rouleau, Guy A.
    van den Berg, Leonard H.
    Van Broeckhoven, Christine
    Rademakers, Rosa
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kubisch, Christian
    A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories2014In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, no 6, p. 419-424Article in journal (Refereed)
    Abstract [en]

    Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

  • 9.
    Alaerts, Maaike
    et al.
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UA), Belgium.
    Venken, Tine
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UA), Belgium.
    Lenaerts, An-Sofie
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UA), Belgium.
    De Zutter, Sonia
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UA), Belgium.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UA), Belgium.
    Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population2006In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 16, no 6, p. 235-236Article in journal (Refereed)
    Abstract [en]

    GPR50 is a G protein-coupled receptor, located on Xq28 and related to the melatonin receptor family. It is suggested as a functional and positional candidate gene for bipolar disorder (BP). Recently an insertion/deletion polymorphism in GPR50, Delta502-505, was found to be associated with BP in a Scottish association sample (P=0.007). When the analysis was restricted to female subjects, the association increased in significance (P=0.00023). We attempted to replicate this finding in a Northern Swedish association sample, but no significant association was detected (P=0.7, women only: P=0.65).

  • 10.
    Albagha, O M E
    et al.
    University of Aberdeen.
    Pettersson, Ulrika
    University of Aberdeen .
    Stewart, A
    University of Aberdeen.
    McGuigan, F E A
    University of Aberdeen.
    MacDonald, H M
    University of Aberdeen.
    Reid, D M
    University of Aberdeen.
    Ralston, S H
    University of Aberdeen.
    Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone.2005In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 42, no 3, p. 240-6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The gene encoding oestrogen receptor alpha (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk.

    OBJECTIVE: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women.

    RESULTS: There was a significant association between a common haplotype "px", defined by the PvuII and XbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were approximately 14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values.

    CONCLUSIONS: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.

  • 11. Ali, Ashfaq
    et al.
    Varga, Tibor V.
    Stojkovic, Ivana A.
    Schulz, Christina-Alexandra
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Barroso, Ines
    Poveda, Alaitz
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Orho-Melander, Marju
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
    Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia?: Findings From the GLACIER and the MDC Studies2016In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 9, no 2, p. 162-171Article in journal (Refereed)
    Abstract [en]

    Background Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability.

    Methods and Results We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmo Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRS(TG)) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRS(TG) were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m(2)) associated with 2.8% (P=8.4x10(-84)) higher triglyceride concentration and each additional WGRS(TG) unit with 2% (P=7.6x10(-48)) higher triglyceride concentration. Each unit of the WGRS(TG) was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (P-interaction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRS(TG)xBMI interaction effect (P-interaction=6.0x10(-4)), which was strengthened by including data from the Danish cohorts (P-interaction=6.5x10(-7)). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRS(TG)xBMIxsex) was observed (P-interaction=0.03), where the WGRS(TG)xBMI interaction was only statistically significant in females. Using protein-protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci.

    Conclusions Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.

  • 12. Almlöf, Jonas Carlsson
    et al.
    Alexsson, Andrei
    Imgenberg-Kreuz, Juliana
    Sylwan, Lina
    Backlin, Christofer
    Leonard, Dag
    Nordmark, Gunnel
    Tandre, Karolina
    Eloranta, Maija-Leena
    Padyukov, Leonid
    Bengtsson, Christine
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Jonsen, Andreas
    Dahlqvist, Solbritt Rantapaa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Sjowall, Christopher
    Bengtsson, Anders A.
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Ronnblom, Lars
    Sandling, Johanna K.
    Syvanen, Ann-Christine
    Novel risk genes for systemic lupus erythematosus predicted by random forest classification2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6236Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

  • 13. Aminoff, Anna
    et al.
    Gunnar, Erika
    Barbaro, Michela
    Mannila, Maria Nastase
    Duponchel, Christiane
    Tosi, Mario
    Robinson, Kristina Lagerstedt
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Ehrenborg, Ewa
    Novel mutations in microsomal triglyceride transfer protein including maternal uniparental disomy in two patients with abetalipoproteinemia2012In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 82, no 2, p. 197-200Article in journal (Refereed)
  • 14.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Is all ALS genetic?2017In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 89, no 3, p. 220-221Article in journal (Other academic)
  • 15. Auer-Grumbach, Michaela
    et al.
    Toegel, Stefan
    Schabhuettl, Maria
    Weinmann, Daniela
    Chiari, Catharina
    Bennett, David L. H.
    Beetz, Christian
    Klein, Dennis
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Boehme, Ilka
    Fink-Puches, Regina
    Gonzalez, Michael
    Harms, Matthew B.
    Motley, William
    Reilly, Mary M.
    Renner, Wilfried
    Rudnik-Schoeneborn, Sabine
    Schlotter-Weigel, Beate
    Themistocleous, Andreas C.
    Weishaupt, Jochen H.
    Ludolph, Albert C.
    Wieland, Thomas
    Tao, Feifei
    Abreu, Lisa
    Windhager, Reinhard
    Zitzelsberger, Manuela
    Strom, Tim M.
    Walther, Thomas
    Scherer, Steven S.
    Zuchner, Stephan
    Martini, Rudolf
    Senderek, Jan
    Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, no 3, p. 607-623Article in journal (Refereed)
    Abstract [en]

    Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade beta-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.

  • 16. Berge-Seidl, Victoria
    et al.
    Pihlstrøm, Lasse
    Maple-Grødem, Jodi
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Larsen, Jan Petter
    Tysnes, Ole-Bjørn
    Toft, Mathias
    The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal2017In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 658, p. 48-52Article in journal (Refereed)
    Abstract [en]

    Objective: Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals. Methods: We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants. Results: We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p = 0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p = 0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p = 0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r(2) 0.95). Conclusions: Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD.

  • 17. Berndt, Sonja I.
    et al.
    Gustafsson, Stefan
    Maegi, Reedik
    Ganna, Andrea
    Wheeler, Eleanor
    Feitosa, Mary F.
    Justice, Anne E.
    Monda, Keri L.
    Croteau-Chonka, Damien C.
    Day, Felix R.
    Esko, Tonu
    Fall, Tove
    Ferreira, Teresa
    Gentilini, Davide
    Jackson, Anne U.
    Luan, Jian'an
    Randall, Joshua C.
    Vedantam, Sailaja
    Willer, Cristen J.
    Winkler, Thomas W.
    Wood, Andrew R.
    Workalemahu, Tsegaselassie
    Hu, Yi-Juan
    Lee, Sang Hong
    Liang, Liming
    Lin, Dan-Yu
    Min, Josine L.
    Neale, Benjamin M.
    Thorleifsson, Gudmar
    Yang, Jian
    Albrecht, Eva
    Amin, Najaf
    Bragg-Gresham, Jennifer L.
    Cadby, Gemma
    den Heijer, Martin
    Eklund, Niina
    Fischer, Krista
    Goel, Anuj
    Hottenga, Jouke-Jan
    Huffman, Jennifer E.
    Jarick, Ivonne
    Johansson, Asa
    Johnson, Toby
    Kanoni, Stavroula
    Kleber, Marcus E.
    Koenig, Inke R.
    Kristiansson, Kati
    Kutalik, Zoltn
    Lamina, Claudia
    Lecoeur, Cecile
    Li, Guo
    Mangino, Massimo
    McArdle, Wendy L.
    Medina-Gomez, Carolina
    Mueller-Nurasyid, Martina
    Ngwa, Julius S.
    Nolte, Ilja M.
    Paternoster, Lavinia
    Pechlivanis, Sonali
    Perola, Markus
    Peters, Marjolein J.
    Preuss, Michael
    Rose, Lynda M.
    Shi, Jianxin
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Smith, Albert Vernon
    Strawbridge, Rona J.
    Surakka, Ida
    Teumer, Alexander
    Trip, Mieke D.
    Tyrer, Jonathan
    Van Vliet-Ostaptchouk, Jana V.
    Vandenput, Liesbeth
    Waite, Lindsay L.
    Zhao, Jing Hua
    Absher, Devin
    Asselbergs, Folkert W.
    Atalay, Mustafa
    Attwood, Antony P.
    Balmforth, Anthony J.
    Basart, Hanneke
    Beilby, John
    Bonnycastle, Lori L.
    Brambilla, Paolo
    Bruinenberg, Marcel
    Campbell, Harry
    Chasman, Daniel I.
    Chines, Peter S.
    Collins, Francis S.
    Connell, John M.
    Cookson, William O.
    de Faire, Ulf
    de Vegt, Femmie
    Dei, Mariano
    Dimitriou, Maria
    Edkins, Sarah
    Estrada, Karol
    Evans, David M.
    Farrall, Martin
    Ferrario, Marco M.
    Ferrieres, Jean
    Franke, Lude
    Frau, Francesca
    Gejman, Pablo V.
    Grallert, Harald
    Groenberg, Henrik
    Gudnason, Vilmundur
    Hall, Alistair S.
    Hall, Per
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Heard-Costa, Nancy L.
    Heath, Andrew C.
    Hebebrand, Johannes
    Homuth, Georg
    Hu, Frank B.
    Hunt, Sarah E.
    Hyppoenen, Elina
    Iribarren, Carlos
    Jacobs, Kevin B.
    Jansson, John-Olov
    Jula, Antti
    Kahonen, Mika
    Kathiresan, Sekar
    Kee, Frank
    Khaw, Kay-Tee
    Kivimaki, Mika
    Koenig, Wolfgang
    Kraja, Aldi T.
    Kumari, Meena
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Laitinen, Jaana H.
    Lakka, Timo A.
    Langenberg, Claudia
    Launer, Lenore J.
    Lind, Lars
    Lindstrom, Jaana
    Liu, Jianjun
    Liuzzi, Antonio
    Lokki, Marja-Liisa
    Lorentzon, Mattias
    Madden, Pamela A.
    Magnusson, Patrik K.
    Manunta, Paolo
    Marek, Diana
    Maerz, Winfried
    Leach, Irene Mateo
    McKnight, Barbara
    Medland, Sarah E.
    Mihailov, Evelin
    Milani, Lili
    Montgomery, Grant W.
    Mooser, Vincent
    Muehleisen, Thomas W.
    Munroe, Patricia B.
    Musk, Arthur W.
    Narisu, Narisu
    Navis, Gerjan
    Nicholson, George
    Nohr, Ellen A.
    Ong, Ken K.
    Oostra, Ben A.
    Palmer, Colin N. A.
    Palotie, Aarno
    Peden, John F.
    Pedersen, Nancy
    Peters, Annette
    Polasek, Ozren
    Pouta, Anneli
    Pramstaller, Peter P.
    Prokopenko, Inga
    Puetter, Carolin
    Radhakrishnan, Aparna
    Raitakari, Olli
    Rendon, Augusto
    Rivadeneira, Fernando
    Rudan, Igor
    Saaristo, Timo E.
    Sambrook, Jennifer G.
    Sanders, Alan R.
    Sanna, Serena
    Saramies, Jouko
    Schipf, Sabine
    Schreiber, Stefan
    Schunkert, Heribert
    Shin, So-Youn
    Signorini, Stefano
    Sinisalo, Juha
    Skrobek, Boris
    Soranzo, Nicole
    Stancakova, Alena
    Stark, Klaus
    Stephens, Jonathan C.
    Stirrups, Kathleen
    Stolk, Ronald P.
    Stumvoll, Michael
    Swift, Amy J.
    Theodoraki, Eirini V.
    Thorand, Barbara
    Tregouet, David-Alexandre
    Tremoli, Elena
    Van der Klauw, Melanie M.
    van Meurs, Joyce B. J.
    Vermeulen, Sita H.
    Viikari, Jorma
    Virtamo, Jarmo
    Vitart, Veronique
    Waeber, Gerard
    Wang, Zhaoming
    Widen, Elisabeth
    Wild, Sarah H.
    Willemsen, Gonneke
    Winkelmann, Bernhard R.
    Witteman, Jacqueline C. M.
    Wolffenbuttel, Bruce H. R.
    Wong, Andrew
    Wright, Alan F.
    Zillikens, M. Carola
    Amouyel, Philippe
    Boehm, Bernhard O.
    Boerwinkle, Eric
    Boomsma, Dorret I.
    Caulfield, Mark J.
    Chanock, Stephen J.
    Cupples, L. Adrienne
    Cusi, Daniele
    Dedoussis, George V.
    Erdmann, Jeanette
    Eriksson, Johan G.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Froguel, Philippe
    Gieger, Christian
    Gyllensten, Ulf
    Hamsten, Anders
    Harris, Tamara B.
    Hengstenberg, Christian
    Hicks, Andrew A.
    Hingorani, Aroon
    Hinney, Anke
    Hofman, Albert
    Hovingh, Kees G.
    Hveem, Kristian
    Illig, Thomas
    Jarvelin, Marjo-Riitta
    Joeckel, Karl-Heinz
    Keinanen-Kiukaanniemi, Sirkka M.
    Kiemeney, Lambertus A.
    Kuh, Diana
    Laakso, Markku
    Lehtimaki, Terho
    Levinson, Douglas F.
    Martin, Nicholas G.
    Metspalu, Andres
    Morris, Andrew D.
    Nieminen, Markku S.
    Njolstad, Inger
    Ohlsson, Claes
    Oldehinkel, Albertine J.
    Ouwehand, Willem H.
    Palmer, Lyle J.
    Penninx, Brenda
    Power, Chris
    Province, Michael A.
    Psaty, Bruce M.
    Qi, Lu
    Rauramaa, Rainer
    Ridker, Paul M.
    Ripatti, Samuli
    Salomaa, Veikko
    Samani, Nilesh J.
    Snieder, Harold
    Sorensen, Thorkild I. A.
    Spector, Timothy D.
    Stefansson, Kari
    Tonjes, Anke
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    Uusitupa, Matti
    van der Harst, Pim
    Vollenweider, Peter
    Wallaschofski, Henri
    Wareham, Nicholas J.
    Watkins, Hugh
    Wichmann, H-Erich
    Wilson, James F.
    Abecasis, Goncalo R.
    Assimes, Themistocles L.
    Barroso, Ines
    Boehnke, Michael
    Borecki, Ingrid B.
    Deloukas, Panos
    Fox, Caroline S.
    Frayling, Timothy
    Groop, Leif C.
    Haritunian, Talin
    Heid, Iris M.
    Hunter, David
    Kaplan, Robert C.
    Karpe, Fredrik
    Moffatt, Miriam F.
    Mohlke, Karen L.
    O'Connell, Jeffrey R.
    Pawitan, Yudi
    Schadt, Eric E.
    Schlessinger, David
    Steinthorsdottir, Valgerdur
    Strachan, David P.
    Thorsteinsdottir, Unnur
    van Duijn, Cornelia M.
    Visscher, Peter M.
    Di Blasio, Anna Maria
    Hirschhorn, Joel N.
    Lindgren, Cecilia M.
    Morris, Andrew P.
    Meyre, David
    Scherag, Andr
    McCarthy, Mark I.
    Speliotes, Elizabeth K.
    North, Kari E.
    Loos, Ruth J. F.
    Ingelsson, Erik
    Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 5, p. 501-U69Article in journal (Refereed)
    Abstract [en]

    Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

  • 18. Berthelot, Claire C
    et al.
    Kamita, Shizuo George
    Sacchi, Romina
    Yang, Jun
    Nording, Malin L
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Entomology, University of California Davis, Davis, CA, United States Of America.
    Georgi, Katrin
    Karbowski, Christine Hegedus
    German, J Bruce
    Weiss, Robert H
    Hogg, Ronald J
    Hammock, Bruce D
    Zivkovic, Angela M
    Changes in PTGS1 and ALOX12 Gene Expression in Peripheral Blood Mononuclear Cells Are Associated with Changes in Arachidonic Acid, Oxylipins, and Oxylipin/Fatty Acid Ratios in Response to Omega-3 Fatty Acid Supplementation2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0144996Article in journal (Refereed)
    Abstract [en]

    Introduction: There is a high degree of inter-individual variability among people in response to intervention with omega-3 fatty acids (FA), which may partly explain conflicting results on the effectiveness of omega-3 FA for the treatment and prevention of chronic inflammatory diseases. In this study we sought to evaluate whether part of this inter-individual variability in response is related to the regulation of key oxylipin metabolic genes in circulating peripheral blood mononuclear cells (PBMCs). Methods: Plasma FA and oxylipin profiles from 12 healthy individuals were compared to PBMC gene expression profiles following six weeks of supplementation with fish oil, which delivered 1.9 g/d eicosapentaenoic acid (EPA) and 1.5 g/d docosahexaenoic acid (DHA). Fold changes in gene expression were measured by a quantitative polymerase chain reaction (qPCR). Results: Healthy individuals supplemented with omega-3 FA had differential responses in prostaglandin-endoperoxide synthase 1 (PTGS1), prostaglandin-endoperoxide synthase 2 (PTGS2), arachidonate 12-lipoxygenase (ALOX12), and interleukin 8 (IL-8) gene expression in isolated PBMCs. In those individuals for whom plasma arachidonic acid (ARA) in the phosphatidylethanolamine (PE) lipid class decreased in response to omega-3 intervention, there was a corresponding decrease in gene expression for PTGS1 and ALOX12. Several oxylipin product/FA precursor ratios (e.g. prostaglandin E-2 (PGE(2))/ARA for PTGS1 and 12-hydroxyeicosatetraenoic acid (12-HETE)/ARA for ALOX12) were also associated with fold change in gene expression, suggesting an association between enzyme activity and gene expression. The fold-change in PTGS1 gene expression was highly positively correlated with ALOX12 gene expression but not with PTGS2, whereas IL-8 and PTGS2 were positively correlated. Conclusions: The regulation of important oxylipin metabolic genes in PBMCs varied with the extent of change in ARA concentrations in the case of PTGS1 and ALOX12 regulation. PBMC gene expression changes in response to omega-3 supplementation varied among healthy individuals, and were associated with changes in plasma FA and oxylipin composition to different degrees in different individuals.

  • 19. Beyder, Arthur
    et al.
    Mazzone, Amelia
    Strege, Peter R.
    Tester, David J.
    Saito, Yuri A.
    Bernard, Cheryl E.
    Enders, Felicity T.
    Ek, Weronica E.
    Schmidt, Peter T.
    Dlugosz, Aldona
    Lindberg, Greger
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ohlsson, Bodil
    Gazouli, Maria
    Nardone, Gerardo
    Cuomo, Rosario
    Usai-Satta, Paolo
    Galeazzi, Francesca
    Neri, Matteo
    Portincasa, Piero
    Bellini, Massimo
    Barbara, Giovanni
    Camilleri, Michael
    Locke, G. Richard, III
    Talley, Nicholas J.
    D'Amato, Mauro
    Ackerman, Michael J.
    Farrugia, Gianrico
    Loss-of-Function of the Voltage-Gated Sodium Channel Na(V)1.5 (Channelopathies) in Patients With Irritable Bowel Syndrome2014In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 146, no 7, p. 1659-1668Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na(V)1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Na(V)1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na(V)1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na(V)1.5 had the greatest effect in reducing Na(V)1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na(V)1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.

  • 20.
    Bhattacharjee, Samsiddhi
    et al.
    Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    Rajaraman, Preetha
    Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    Jacobs, Kevin B
    Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.
    Wheeler, William A
    Information Management Services, Rockville, MD 20852, USA.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hartge, Patricia
    Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    GliomaScan Consortium,
    GliomaScan Consortium investigators and affiliations are available in the Supplemental Data.
    Yeager, Meredith
    Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.
    Chung, Charles C
    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    Chanock, Stephen J
    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    Chatterjee, Nilanjan
    Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits2012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 5, p. 821-835Article in journal (Refereed)
    Abstract [en]

    Pooling genome-wide association studies (GWASs) increases power but also poses methodological challenges because studies are often heterogeneous. For example, combining GWASs of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical approaches for meta-analysis or pooled analysis, however, might not be suitable for such analysis because individual variants are likely to be associated with only a subset of the traits or might demonstrate effects in different directions. We propose a method that exhaustively explores subsets of studies for the presence of true association signals that are in either the same direction or possibly opposite directions. An efficient approximation is used for rapid evaluation of p values. We present two illustrative applications, one for a meta-analysis of separate case-control studies of six distinct cancers and another for pooled analysis of a case-control study of glioma, a class of brain tumors that contains heterogeneous subtypes. Both the applications and additional simulation studies demonstrate that the proposed methods offer improved power and more interpretable results when compared to traditional methods for the analysis of heterogeneous traits. The proposed framework has applications beyond genetic association studies.

  • 21.
    Birve, Anna
    Umeå University, Faculty of Medicine, Molecular Biology.
    Suppressor of zeste 12, a Polycomb group gene in Drosophila melanogaster; one piece in the epigenetic puzzle2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In multicellular organisms all cells in one individual have an identical genotype, and yet their bodies consist of many and very different tissues and thus many different cell types. Somehow there must be a difference in how genes are interpreted. So, there must be signals that tell the genes when and where to be active and inactive, respectively. In some instances a specific an expression pattern (active or inactive) is epigenetic; it is established and maintained throughout multiple rounds of cell divisions. In the developing Drosophila embryo, the proper expression pattern of e.g. the homeotic genes Abd-B and Ubx is to be kept active in the posterior part and silenced in the anterior. Properly silenced homeotic genes are crucial for the correct segmentation pattern of the fly and the Polycomb group (Pc-G) proteins are vital for maintaining this type of stable repression.

    As part of this thesis, Suppressor of zeste 12 (Su(z)12) is characterized as a Drosophila Pc-G gene. Mutations in the gene cause widespread misexpression of several homeotic genes in embryos and larvae. Results show that the silencing of the homeotic genes Abd-B and Ubx, probably is mediated via physical binding of SU(Z)12 to Polycomb Response Elements in the BX-C. Su(z)12 mutations are strong suppressors of position-effect-variegation and the SU(Z)12 protein binds weakly to the heterochromatic centromeric region. These results indicate that SU(Z)12 has a function in heterochromatin-mediated repression, which is an unusual feature for a Pc-G protein. The structure of the Su(z)12 gene was determined and the deduced protein contains a C2-H2 zinc finger domain, several nuclear localization signals, and a region, the VEFS box, with high homology to mammalian and plant homologues. Su(z)12 was originally isolated in a screen for modifiers of the zeste-white interaction and I present results that suggests that this effect is mediated through an interaction between Su(z)12 and zeste. I also show that Su(z)12 interact genetically with other Pc-G mutants and that the SU(Z)12 protein binds more than 100 euchromatic bands on polytene chromosomes. I also present results showing that SU(Z)12 is a subunit of two different E(Z)/ESC embryonic silencing complexes, one 1MDa and one 600 kDa complex, where the larger complex also contains PCL and RPD3.

    In conclusion, results presented in this thesis show that the recently identified Pc-G gene, Su(z)12, is of vital importance for correct maintenance of silencing of the developmentally important homeotic genes.

  • 22. Blasco, Helene
    et al.
    Bernard-Marissal, Nathalie
    Vourc'h, Patrick
    Guettard, Yves Olivier
    Sunyach, Claire
    Augereau, Olivier
    Khederchah, Joelle
    Mouzat, Kevin
    Antar, Catherine
    Gordon, Paul H.
    Veyrat-Durebex, Charlotte
    Besson, Gerard
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Salachas, Francois
    Meininger, Vincent
    Camu, William
    Pettmann, Brigitte
    Andres, Christian R.
    Corcia, Philippe
    A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS2013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 7, p. 953-960Article in journal (Refereed)
    Abstract [en]

    The dihydropyrimidinase-like 3 (DPYSL3) or Collapsin Response Mediator Protein 4a (CRMP4a) expression is modified in neurodegeneration and is involved in several ALS-associated pathways including axonal transport, glutamate excitotoxicity, and oxidative stress. The objective of the study was to analyze CRMP4 as a risk factor for ALS. We analyzed the DPYSL3/CRMP4 gene in French ALS patients (n=468) and matched-controls (n=394). We subsequently examined a variant in a Swedish population (184 SALS, 186 controls), and evaluated its functional effects on axonal growth and survival in motor neuron cell culture. The rs147541241:A>G missense mutation occurred in higher frequency among French ALS patients (odds ratio=2.99) but the association was not confirmed in the Swedish population. In vitro expression of mutated DPYSL3 in motor neurons reduced axonal growth and accelerated cell death compared with wild type protein. Thus, the association between the rs147541241 variant and ALS was limited to the French population, highlighting the geographic particularities of genetic influences (risks, contributors). The identified variant appears to shorten motor neuron survival through a detrimental effect on axonal growth and CRMP4 could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development.

  • 23. Blaydon, Diana C
    et al.
    Lind, Lisbet K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Plagnol, Vincent
    Linton, Kenneth J
    Smith, Francis JD
    Wilson, Neil J
    McLean, WH Irwin
    Munro, Colin S
    South, Andrew P
    Leigh, Irene M
    O'Toole, Edel A
    Lundström, Anita
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Kelsell, David P
    Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 2, p. 330-335Article in journal (Refereed)
  • 24. Blink, Marjolein
    et al.
    Zimmermann, Martin
    von Neuhoff, Christine
    Reinhardt, Dirk
    de Haas, Valerie
    Hasle, Henrik
    O'Brien, Maureen M
    Stark, Batia
    Tandonnet, Julie
    Pession, Andrea
    Tousovska, Katerina
    Cheuk, Daniel K L
    Kudo, Kazuko
    Taga, Takashi
    Rubnitz, Jeffrey E
    Haltrich, Iren
    Balwierz, Walentyna
    Pieters, Rob
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Johansson, Bertil
    van den Heuvel-Eibrink, Marry M
    Zwaan, C Michel
    Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study2014In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 2, p. 299-307Article in journal (Refereed)
    Abstract [en]

    Myeloid leukemia of Down syndrome has a better prognosis than sporadic pediatric acute myeloid leukemia. Most cases of myeloid leukemia of Down syndrome are characterized by additional cytogenetic changes besides the constitutional trisomy 21, but their potential prognostic impact is not known. We, therefore, conducted an international retrospective study of clinical characteristics, cytogenetics, treatment, and outcome of 451 children with myeloid leukemia of Down syndrome. All karyotypes were centrally reviewed before assigning patients to subgroups. The overall 7-year event-free survival for the entire cohort was 78% (± 2%), with the overall survival rate being 79% (± 2%), the cumulative incidence of relapse 12% (± 2%), and the cumulative incidence of toxic death 7% (± 1%). Outcome estimates showed large differences across the different cytogenetic subgroups. Based on the cumulative incidence of relapse, we could risk-stratify patients into two groups: cases with a normal karyotype (n=103) with a higher cumulative incidence of relapse (21%± 4%) than cases with an aberrant karyotype (n=255) with a cumulative incidence of relapse of 9% (± 2%) (P=0.004). Multivariate analyses revealed that white blood cell count ≥ 20 × 10(9)/L and age >3 years were independent predictors for poor event-free survival, while normal karyotype independently predicted inferior overall survival, event-free survival, and relapse-free survival. In conclusion, this study showed large differences in outcome within patients with myeloid leukemia of Down syndrome and identified novel prognostic groups that predicted clinical outcome and hence may be used for stratification in future treatment protocols.

  • 25. Bonaïti, Bernard
    et al.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bonaïti-Pellié, Catherine
    Planté-Bordeneuve, Violaine
    TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n=33) and Swedish families (n=86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.

  • 26.
    Brännström, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sirkka, S.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Induction of ubiquilin differs between different SOD1 transgenic strains2014In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 40, no S1, p. 22-22Article in journal (Other academic)
  • 27.
    Bäckström, Stefan
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    The hematopoietic transcription factor RUNX1: a structural view2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The malfunction of the transcriptional regulator RUNX1 is the major cause of several variants of acute human leukemias and its normal function is to regulate the development of the blood system in concert with other transcriptional co-regulators. RUNX1 belongs to a conserved family of heterodimeric transcription factors that share a conserved DNA binding domain, the Runt domain (RD), named after the first member of this group – Runt - found in Drosophila melanogaster. The binding partner CBFβ serves as a regulator of RUNX by enhancing its DNA binding affinity through an allosteric mechanism.

    The main focus ofo my thesis work has been the crystallization and structural analysis of the RUNX1 RD and involved also more technical methodological aspects that can be applied to X-ray crystallography in general.

    The high resolution crystal structure of the free RD shows that this immunoglobulin-like molecule undergoes significant structural changes upon binding to both CBFβ and DNA. This involves a large flip of the L11 loop from a closed conformation in the free protein to an open conformation when CBFβ and/or DNA are bound. We refer to this transition as the “S-switch”. Smaller but significant conformational changes in other parts of the RD accompany the “S-switch”. We suggest that CBFβ triggers and stabilizes the “S-switch” which leads to the conversion of the RD into a conformation enhanced for DNA binding.

    During the structural analysis of the RD we identified two chloride ions that are coordinated by residues otherwise involved in DNA binding. In electrophoretic mobility-shift analyses (EMSA) we demonstrated a chloride ion concentration dependent stimulation of the DNA binding affinity of RUNX1. We further showed by NMR line width broadening experiments that the chloride binding occurred within the physiological range. A comparable DNA binding stimulation of RUNX1 was seen in the presence of negative amino acids. This suggests a regulation of the DNA binding activity of RUNX1 proteins through acidic amino acid residues possibly provided by activation domains of transcriptional co-regulators that interact with RUNX1.

    The use of the anomalous signal from halide ions has become a powerful technique for obtaining phase information. By replacing the sodium chloride with potassium bromide in the crystallisation conditions of the RD, we could demonstrate in a single wavelength anomalous diffraction (SAD) experiment that the anomalous signal from 2 bromide ions were sufficient to phase a 16 kDa protein. Due to lack of completeness in the low-resolution shells caused by overloaded intensities, density modification schemes failed and the resulting electron density maps were not interpretable. By combining the highresolution

    synchrotron data with low-resolution data from a native data set collected on a home X-ray source, the density modified bromide phases gave easily traceable maps.

  • 28. Cammaerts, Sophia
    et al.
    Strazisar, Mojca
    Smets, Bart
    Weckhuysen, Sarah
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    De Jonghe, Peter
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    De Rijk, Peter
    Del Favero, Jurgen
    Schizophrenia-Associated MIR204 Regulates Noncoding RNAs and Affects Neurotransmitter and Ion Channel Gene Sets2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0144428Article in journal (Refereed)
    Abstract [en]

    As regulators of gene expression, microRNAs (miRNAs) are likely to play an important role in the development of disease. In this study we present a large-scale strategy to identify miRNAs with a role in the regulation of neuronal processes. Thereby we found variant rs7861254 located near the MIR204 gene to be significantly associated with schizophrenia. This variant resulted in reduced expression of miR-204 in neuronal-like SH-SY5Y cells. Analysis of the consequences of the altered miR-204 expression on the transcriptome of these cells uncovered a new mode of action for miR-204, being the regulation of noncoding RNAs (ncRNAs), including several miRNAs, such as MIR296. Furthermore, pathway analysis showed downstream effects of miR-204 on neurotransmitter and ion channel related gene sets, potentially mediated by miRNAs regulated through miR-204.

  • 29. Campa, Daniele
    et al.
    Barrdahl, Myrto
    Gaudet, Mia M.
    Black, Amanda
    Chanock, Stephen J.
    Diver, W. Ryan
    Gapstur, Susan M.
    Haiman, Christopher
    Hankinson, Susan
    Hazra, Aditi
    Henderson, Brian
    Hoover, Robert N.
    Hunter, David J.
    Joshi, Amit D.
    Kraft, Peter
    Le Marchand, Loic
    Lindstrom, Sara
    Willett, Walter
    Travis, Ruth C.
    Amiano, Pilar
    Siddiq, Afshan
    Trichopoulos, Dimitrios
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Tjonneland, Anne
    Weiderpass, Elisabete
    Peeters, Petra H.
    Panico, Salvatore
    Dossus, Laure
    Ziegler, Regina G.
    Canzian, Federico
    Kaaks, Rudolf
    Genetic risk variants associated with in situ breast cancer2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, article id 82Article in journal (Refereed)
    Abstract [en]

    Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS.

    Methods: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile.

    Results: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies.

    Conclusions: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.

  • 30.
    Campino, Susana
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Genetic analysis of murine malaria2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria, an infectious disease caused by Plasmodium parasites, is one of the major world-scale health problems. Despite the efforts aimed at finding an effective way to control the disease, the success has been thwarted by the emergence of parasite drug resistance and mosquito resistance to insecticides. This thesis focuses on the genetic analysis of resistance to murine malaria induced by the lethal Plasmodium berghei ANKA using a wild-derived-inbred strain (WDIS). The aim of this thesis was to exploit the genetic diversity represented among WDIS for identifying loci contributing to resistance/susceptibility to murine malaria.

    The work included a genome-wide polymorphism survey using microsatellite markers performed on 10 WDIS. Comparisons of these strains to laboratory inbred strains confirmed a higher rate of polymorphism among the WDIS. We conclude that these WDIS represent repositories of unique naturally occurring genetic variability that may prove to be invaluable for the study of complex phenotypes. Next, we used the WDIS to search for novel phenotypes related to malaria pathogenesis. Whereas most laboratory strains were susceptible to experimental cerebral malaria (ECM) after infection with P. berghei ANKA, several WDIS were found to be resistant. To study the genetic inheritance of resistant/susceptibility to P. berghei ANKA infection we analysed backcross and F2 cohorts derived from crossing the WLA wild-derived strain with a laboratory mouse strain (C57BL/6). A novel phenotype represented by the cure of infection, clearance of parasitaemia and establishment of immunological memory was observed in the F2 progeny. The backcross progeny was used to genetically map one locus on chromosome 1 (Berr1) and one locus on chromosome 11 (Berr2) that mediate control of resistance to ECM induced by P. berghei ANKA. Genetic mapping using the F2 progeny showed that a locus on chromosome 1 (Berr1) and a locus on chromosome 9 (Berr3) were contributing to control survival time after infection with lethal Plasmodium. Finally, we identified, a locus on chromosome 4 (Berr4) that appears to control time of death due to hyperparasitaemia.

    This thesis underlines the value of using WDIS to reveal genetic factors involved in the aetiology of disease phenotypes. The characterisation of the genetic factors represented by the malaria resistance loci identified here are expected to provide a better understanding of the malaria pathology.

  • 31.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Genetic and epidemiological studies of hereditary colorectal cancer2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) is the most common hereditary syndrome predisposing to colorectal cancer, accounting for 1-3% of all colorectal cancer. This multi-organ cancer predisposition syndrome is caused by mutations in the mismatch repair (MMR) genes, especially MLH1 and MSH2, and to lesser extents MSH6 and PMS2, which lead to widespread genetic instability and thus microsatellite instability (MSI). Hereditary cancer often manifests in two or more tumours in a single individual; 35-40% of Lynch syndrome patients have synchronous or metachronous tumours of the two major Lynch syndrome-related cancers: colorectal and endometrial.

    The main purposes of the work underlying this thesis were to identify persons at risk of Lynch syndrome or other types of hereditary colorectal cancer, to estimate the cancer risks associated with these predispositions and to identify the underlying genetic causes.

    A population-based cohort of 78 persons with double primary colorectal or colorectal and endometrial cancer was identified. Cancer risks in their 649 first-degree relatives were estimated in relation to tumour MSI status (positive or negative) and age at diagnosis (before or after 50 years of age) in the probands. The overall standardised incidence ratio was 1.69 (95% CI; 1.39-2.03). The highest risks for Lynch syndrome-associated cancers: (colorectal, endometrial, ovarian and gastric) were found in families with young MSI-positive probands, likely representing Lynch syndrome families. Importantly, no overall risk was found in families with old probands, irrespective of MSI status.

    Blood samples were available from 24 MSI-positive patients for mutation screening of MLH1, MSH2 and MSH6. Sequence variants or rearrangements predicted to affect protein function were found in 16 patients. Six novel variants were found: two large rearrangements, two truncating and two missense mutations. The missense mutations were found to segregate in the families. Studies of allele frequencies, MSI and loss of immunostaning in tumours from family members further supports the hypothesis that these missense changes play a role in Lynch syndrome, as do the non-conservative nature and evolutionary conservation of the amino acid exchanges. Five families had mutations in MLH1, five in MSH2, and six in MSH6. The unexpectedly large impact of MSH6 was in genealogical studies shown to be due to a founder effect. Cumulative risk studies showed that the MSH6 families, despite their late age of onset, have a high lifetime risk for all Lynch syndrome-related cancers, significantly higher in women (89% by age 80 years) than in men (69%). The gender differences are in part due to high endometrial (70%) and ovarian cancer risk (33%) in addition to the high colorectal cancer risk (60%). These findings are of great importance for counselling and surveillance of families with MSH6 mutations.

    Finally, in a large family with MSI-negative hereditary colorectal cancer for which the MMR genes and APC had been excluded as possible causes, a genome-wide linkage analysis was performed, resulting in a suggested linkage to chromosome 7.

    Conclusions: Relatives of probands with MSI-positive, double primary colorectal and endometrial cancer diagnosed before the age of 50 years have significantly increased risks of Lynch syndrome-related cancers. MSH6 mutations, which have unusually high impact in this study population due to a founder effect, confer high cumulative risks of cancer despite the generally late age of onset.

  • 32.
    Charpentier, Emmanuelle
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Richter, Hagen
    van der Oost, John
    White, Malcolm F.
    Biogenesis pathways of RNA guides in archaeal and bacterial CRISPR-Cas adaptive immunity2015In: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 39, no 3, p. 428-441Article, review/survey (Refereed)
    Abstract [en]

    CRISPR-Cas is an RNA-mediated adaptive immune system that defends bacteria and archaea against mobile genetic elements. Short mature CRISPR RNAs (crRNAs) are key elements in the interference step of the immune pathway. A CRISPR array composed of a series of repeats interspaced by spacer sequences acquired from invading mobile genomes is transcribed as a precursor crRNA (pre-crRNA) molecule. This pre-crRNA undergoes one or two maturation steps to generate the mature crRNAs that guide CRISPR-associated (Cas) protein(s) to cognate invading genomes for their destruction. Different types of CRISPR-Cas systems have evolved distinct crRNA biogenesis pathways that implicate highly sophisticated processing mechanisms. In Types I and III CRISPR-Cas systems, a specific endoribonuclease of the Cas6 family, either standalone or in a complex with other Cas proteins, cleaves the pre-crRNA within the repeat regions. In Type II systems, the trans-acting small RNA (tracrRNA) base pairs with each repeat of the pre-crRNA to form a dual-RNA that is cleaved by the housekeeping RNase III in the presence of the protein Cas9. In this review, we present a detailed comparative analysis of pre-crRNA recognition and cleavage mechanisms involved in the biogenesis of guide crRNAs in the three CRISPR-Cas types.

  • 33. Chen, Chi-Hua
    et al.
    Wang, Yunpeng
    Lo, Min-Tzu
    Schork, Andrew
    Fan, Chun-Chieh
    Holland, Dominic
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Center for Multimodal Imaging and Genetics, Department of Radiology, University of California, San Diego, La Jolla, California, USA.
    Smeland, Olav B.
    Djurovic, Srdjan
    Sanyal, Nilotpal
    Hibar, Derrek P.
    Thompson, Paul M.
    Thompson, Wesley K.
    Andreassen, Ole A.
    Dale, Anders M.
    Leveraging genome characteristics to improve gene discovery for putamen subcortical brain structure2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15736Article in journal (Refereed)
    Abstract [en]

    Discovering genetic variants associated with human brain structures is an on-going effort. The ENIGMA consortium conducted genome-wide association studies (GWAS) with standard multi-study analytical methodology and identified several significant single nucleotide polymorphisms (SNPs). Here we employ a novel analytical approach that incorporates functional genome annotations (e.g., exon or 5′UTR), total linkage disequilibrium (LD) scores and heterozygosity to construct enrichment scores for improved identification of relevant SNPs. The method provides increased power to detect associated SNPs by estimating stratum-specific false discovery rate (FDR), where strata are classified according to enrichment scores. Applying this approach to the GWAS summary statistics of putamen volume in the ENIGMA cohort, a total of 15 independent significant SNPs were identified (conditional FDR < 0.05). In contrast, 4 SNPs were found based on standard GWAS analysis (P < 5 × 10−8). These 11 novel loci include GATAD2B, ASCC3, DSCAML1, and HELZ, which are previously implicated in various neural related phenotypes. The current findings demonstrate the boost in power with the annotation-informed FDR method, and provide insight into the genetic architecture of the putamen.

  • 34. Chien, Yin-Hsiu
    et al.
    Abdenur, Jose E.
    Baronio, Federico
    Bannick, Allison Anne
    Corrales, Fernando
    Couce, Maria
    Donner, Markus G.
    Ficicioglu, Can
    Freehauf, Cynthia
    Frithiof, Deborah
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gotway, Garrett
    Hirabayashi, Koichi
    Hofstede, Floris
    Hoganson, George
    Hwu, Wuh-Liang
    James, Philip
    Kim, Sook
    Korman, Stanley H.
    Lachmann, Robin
    Levy, Harvey
    Lindner, Martin
    Lykopoulou, Lilia
    Mayatepek, Ertan
    Muntau, Ania
    Okano, Yoshiyuki
    Raymond, Kimiyo
    Rubio-Gozalbo, Estela
    Scholl-Buergi, Sabine
    Schulze, Andreas
    Singh, Rani
    Stabler, Sally
    Stuy, Mary
    Thomas, Janet
    Wagner, Conrad
    Wilson, William G.
    Wortmann, Saskia
    Yamamoto, Shigenori
    Pao, Maryland
    Blom, Henk J.
    Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes2015In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 10, article id 99Article in journal (Refereed)
    Abstract [en]

    Background: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine beta-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities. Purpose of the study: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence. Results and Discussion: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 mu M or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.

  • 35. Corbin, Laura J.
    et al.
    Tan, Vanessa Y.
    Hughes, David A.
    Wade, Kaitlin H.
    Paul, Dirk S.
    Tansey, Katherine E.
    Butcher, Frances
    Dudbridge, Frank
    Howson, Joanna M.
    Jallow, Momodou W.
    John, Catherine
    Kingston, Nathalie
    Lindgren, Cecilia M.
    O'Donavan, Michael
    O'Rahilly, Stephen
    Owen, Michael J.
    Palmer, Colin N. A.
    Pearson, Ewan R.
    Scott, Robert A.
    van Heel, David A.
    Whittaker, John
    Frayling, Tim
    Tobin, Martin D.
    Wain, Louise V.
    Smith, George Davey
    Evans, David M.
    Karpe, Fredrik
    McCarthy, Mark I.
    Danesh, John
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, SE-205 02, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
    Timpson, Nicholas J.
    Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 711Article, review/survey (Refereed)
    Abstract [en]

    Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

  • 36. Dahgam, Santosh
    et al.
    Modig, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Naluai, Asa Torinsson
    Olin, Anna-Carin
    Nyberg, Fredrik
    Haplotypes of the inducible nitric oxide synthase gene are strongly associated with exhaled nitric oxide levels in adults: a population-based study2014In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, no 7, p. 449-454Article in journal (Refereed)
    Abstract [en]

    Background Previous genetic association studies have reported evidence for association of single-nucleotide polymorphisms (SNPs) in the NOS2 gene, encoding inducible nitric oxide synthase (iNOS), to variation in levels of fractional exhaled nitric oxide (FENO) in children and adults. In this study, we evaluated 10 SNPs in the region of chromosome 17 from 26.07Mb to 26.13Mb to further understand the contribution of NOS2 to variation in levels of FENO. Methods In a cohort of 5912 adults 25-75years of age, we investigated the relationship between NOS2 haplotypes and FENO, and effect modification by asthma. Results Seven common (frequency 5%) haplotypes (H1-H7) were inferred from all possible haplotype combinations. One haplotype (H3) was significantly associated with lower levels of FENO: -5.8% (95% CI -9.8 to -1.7; p=0.006) compared with the most common baseline haplotype H1. Two haplotypes (H5 and H6) were significantly associated with higher levels of FENO: +10.7% (95% CI 5.0 to 16.7; p=0.0002) and +14.9% (95% CI 10.6 to 19.3; p=7.8x10(-13)), respectively. The effect of haplotype H3 was mainly seen in subjects with asthma (-21.6% (95% CI -33.5 to -5.9)) and was not significant in subjects without asthma (-4.2% (95% CI -8.4 to 0.2)). The p value for interaction between H3 and asthma status was 0.004. Conclusions Our findings suggest that several common haplotypes in the NOS2 gene contribute to variation in FENO in adults. We also saw some evidence of effect modification by asthma status on haplotype H3.

  • 37. Dahgam, Santosh
    et al.
    Nyberg, Fredrik
    Modig, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Naluai, Åsa Torinsson
    Olin, Anna-Carin
    Single nucleotide polymorphisms in the NOS2 and NOS3 genes are associated with exhaled nitric oxide2012In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 49, no 3, p. 200-205Article in journal (Refereed)
    Abstract [en]

    Background Polymorphisms in nitric oxide synthase genes (NOS1, NOS2, and NOS3) have been suggested to have a major impact on fraction of exhaled nitric oxide (FENO), a biomarker of airway inflammation. However, the genetic contribution of NOS polymorphisms to FENO is not fully understood. The aim of this study was to investigate comprehensively the association between single nucleotide polymorphisms (SNPs) in all three NOS genes and FENO in an adult population, and to assess whether such associations are modified by asthma or atopy.

    Method In 1737 adults from a Swedish general population sample, FENO was measured and genetic variation in the NOS genes was assessed using 49 SNPs. The genetic effect of NOS polymorphisms on FENO, asthma, and atopy was estimated using multiple regression methods.

    Results In a multi-SNP model based on stepwise regression analysis, two SNPs in NOS2 and one in NOS3 showed independent associations with levels of FENO. For NOS2 SNP rs9901734, subjects had 5.3% (95% CI 1.0% to 9.7%) higher levels of FENO per G allele, and for rs3729508, subjects with CC or CT genotypes had 9.4% (95% CI 3.1% to 15.2%) higher levels compared with TT. For NOS3 SNP rs7830, subjects with GT or TT had 5.6% (95% CI 0.4% to 11.1%) higher levels than GG; the genetic effect of this SNP was stronger in asthmatics (21.9%, 95% CI 4.6% to 42.0%).

    Conclusion These results suggest that NOS2 is the major NOS gene determining variability in exhaled nitric oxide in the healthy adult population, while NOS3 may play a more important role in asthmatic adults.

  • 38.
    Dahl, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Stem cell function and organ development: analysis of Lhx2 function in hematopoietic stem cells and eye development2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    When a multicellular organism suffers damages to tissues/organs it heals itself by either substituting the lost cellular matrix by scar formation or by regenerating the lost tissue. Regeneration likely occurs by a recapitulation of the developmental process that formed the organ. Many processes regulating organ development are based on epithelial-mesenchymal interactions and a strict control of organ specific stem/progenitor cells. Elucidation of the molecular basis of these processes is therefore vital in order to develop novel therapies in regenerative medicine. The LIM homebox gene Lhx2 is interesting in this context since Lhx2 has been shown to be important for the formation of several organs by regulating epithelial-mesenchymal interactions and progenitor cell function. Targeted inactivation of Lhx2 leads to a lethal anemia due to malformed liver and severe neural abnormalities such as hypoplasia of the forebrain and anophtalmia. Thus, elucidation of the mechanisms of the function of Lhx2 in different organ systems would give important insights into the molecular mechanisms regulating epithelial-mesenchymal interactions and stem/progenitor cell function.

    To elucidate the function of Lhx2 in the hematopoietic system Lhx2 was initially expressed in hematopoietic progenitor cells derived from ES cells differentiated in vitro using retroviral vectors. This approach led to the generation of hematopoietic stem cell (HSC)-like cell lines suggesting that Lhx2 could impact HSC function. However neither the specificity nor the efficiency of the Lhx2-induced phenotype could be determined using this approach. To be able to elucidate the function of Lhx2 in the hematopoietic system, an ES cell line with inducible Lhx2 expression was generated. Lhx2 expression induces self-renewal of a distinct hematopoietic progenitor cell from which HSC-like cell lines were established. Down-regulation of Lhx2 in these HSC-like cell lines leads to a rapid loss of stem cell character, providing a good model to study the molecular function of Lhx2 in hematopoietic stem/progenitor cells. A global gene expression analysis was performed comparing the Lhx2+ stem cell population to the Lhx2- differentiated progeny. This approach identified genes putatively linked to self-renewal/differentiation of HSCs. A considerable proportion of the genes showed an overlapping gene expression pattern with Lhx2 expression in tissue of non-hematopoietic origin suggesting that Lhx2 function in stem/progenitor cells partly overlap with Lhx2 function during organ development.

    In order to define other Lhx2-dependent progenitor cell populations and to generate a tool to analyze the function of Lhx2 in organ development a new transgenic mouse model was generated. By using a specific part of the Lhx2 promoter to drive expression of Cre recombinase in vivo (Lhx2-Cre mice) we have been able to define the first eye committed progenitor cells in the forebrain. By using the Lhx2-Cre mice it will be possible to distinguish the function of genes during eye development from their function in the patterning of the forebrain e.g. the eye field transcription factors. Conditional inactivation of Lhx2 in these eye specific progenitor cells causes an immediate developmental arrest. The transgene is also active in Lhx2-/- embryonic forebrain, but re-expression of Lhx2 in Lhx2-/- progenitor cells only promote formation of retinal pigment epithelium cells. Analysis of genes expressed by the Lhx2+ stem cell population allowed us to define novel genes putatively linked to Lhx2 function in eye development. Thus, we have defined the progenitor cells in the forebrain committed to eye development and the expansion and patterning of these progenitors are dependent on Lhx2. Although commitment to eye development is Lhx2-independent, Lhx2 might be important for the acquisition of the oligopotent fate of these progenitor cells.

  • 39.
    Danielsson, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Coates, Philip J
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ebrahimi, Majid
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Genes Involved in Epithelial Differentiation and Development are Differentially Expressed in Oral and Genital Lichen Planus Epithelium Compared to Normal Epithelium2014In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 94, no 5, p. 526-530Article in journal (Refereed)
    Abstract [en]

    Lichen planus (LP) is a chronic mucocutaneous disease with unknown cause. Patients with LP often have both oral and genital lesions, but these conditions are often considered as separate diseases and treated accordingly. To find out which genes are differently expressed in mucosal LP compared to normal mucosa and establish whether oral and genital LP are in fact the same disease, whole genome expression analysis was performed on epithelium from 13 patients diagnosed with oral and/or genital LP and normal controls. For confirmation of keratin 4 and corneodesmosin expression, quantitative reverse-transcription PCR and immunohistochemistry were used. Many genes involved in epithelial development and differentiation are differently expressed in epithelium from LP compared to normal epithelium. Several of the differentially expressed genes are common for oral and genital LP and the same biological processes are altered which supports the fact that oral and genital LP are manifestations of the same disease. The change in gene expression indicates that differentiation is altered leading to changes in the epithelial barrier.

  • 40. Davies, Gail
    et al.
    Lam, Max
    Harris, Sarah E.
    Trampush, Joey W.
    Luciano, Michelle
    Hill, W. David
    Hagenaars, Saskia P.
    Ritchie, Stuart J.
    Marioni, Riccardo E.
    Fawns-Ritchie, Chloe
    Liewald, David C. M.
    Okely, Judith A.
    Ahola-Olli, Ari V.
    Barnes, Catriona L. K.
    Bertram, Lars
    Bis, Joshua C.
    Burdick, Katherine E.
    Christoforou, Andrea
    DeRosse, Pamela
    Djurovic, Srdjan
    Espeseth, Thomas
    Giakoumaki, Stella
    Giddaluru, Sudheer
    Gustavson, Daniel E.
    Hayward, Caroline
    Hofer, Edith
    Ikram, M. Arfan
    Karlsson, Robert
    Knowles, Emma
    Lahti, Jari
    Leber, Markus
    Li, Shuo
    Mather, Karen A.
    Melle, Ingrid
    Morris, Derek
    Oldmeadow, Christopher
    Palviainen, Teemu
    Payton, Antony
    Pazoki, Raha
    Petrovic, Katja
    Reynolds, Chandra A.
    Sargurupremraj, Muralidharan
    Scholz, Markus
    Smith, Jennifer A.
    Smith, Albert V.
    Terzikhan, Natalie
    Thalamuthu, Anbupalam
    Trompet, Stella
    van der Lee, Sven J.
    Ware, Erin B.
    Windham, B. Gwen
    Wright, Margaret J.
    Yang, Jingyun
    Yu, Jin
    Ames, David
    Amin, Najaf
    Amouyel, Philippe
    Andreassen, Ole A.
    Armstrong, Nicola J.
    Assareh, Amelia A.
    Attia, John R.
    Attix, Deborah
    Avramopoulos, Dimitrios
    Bennett, David A.
    Boehmer, Anne C.
    Boyle, Patricia A.
    Brodaty, Henry
    Campbell, Harry
    Cannon, Tyrone D.
    Cirulli, Elizabeth T.
    Congdon, Eliza
    Conley, Emily Drabant
    Corley, Janie
    Cox, Simon R.
    Dale, Anders M.
    Dehghan, Abbas
    Dick, Danielle
    Dickinson, Dwight
    Eriksson, Johan G.
    Evangelou, Evangelos
    Faul, Jessica D.
    Ford, Ian
    Freimer, Nelson A.
    Gao, He
    Giegling, Ina
    Gillespie, Nathan A.
    Gordon, Scott D.
    Gottesman, Rebecca F.
    Griswold, Michael E.
    Gudnason, Vilmundur
    Harris, Tamara B.
    Hartmann, Annette M.
    Hatzimanolis, Alex
    Heiss, Gerardo
    Holliday, Elizabeth G.
    Joshi, Peter K.
    Kahonen, Mika
    Kardia, Sharon L. R.
    Karlsson, Ida
    Kleineidam, Luca
    Knopman, David S.
    Kochan, Nicole A.
    Konte, Bettina
    Kwok, John B.
    Le Hellard, Stephanie
    Lee, Teresa
    Lehtimaki, Terho
    Li, Shu-Chen
    Liu, Tian
    Koini, Marisa
    London, Edythe
    Longstreth, Will T., Jr.
    Lopez, Oscar L.
    Loukola, Anu
    Luck, Tobias
    Lundervold, Astri J.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lyytikainen, Leo-Pekka
    Martin, Nicholas G.
    Montgomery, Grant W.
    Murray, Alison D.
    Need, Anna C.
    Noordam, Raymond
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ollier, William
    Papenberg, Goran
    Pattie, Alison
    Polasek, Ozren
    Poldrack, Russell A.
    Psaty, Bruce M.
    Reppermund, Simone
    Riedel-Heller, Steffi G.
    Rose, Richard J.
    Rotter, Jerome I.
    Roussos, Panos
    Rovio, Suvi P.
    Saba, Yasaman
    Sabb, Fred W.
    Sachdev, Perminder S.
    Satizabal, Claudia L.
    Schmid, Matthias
    Scott, Rodney J.
    Scult, Matthew A.
    Simino, Jeannette
    Slagboom, P. Eline
    Smyrnis, Nikolaos
    Soumare, Aicha
    Stefanis, Nikos C.
    Stott, David J.
    Straub, Richard E.
    Sundet, Kjetil
    Taylor, Adele M.
    Taylor, Kent D.
    Tzoulaki, Ioanna
    Tzourio, Christophe
    Uitterlinden, Andre
    Vitart, Veronique
    Voineskos, Aristotle N.
    Kaprio, Jaakko
    Wagner, Michael
    Wagner, Holger
    Weinhold, Leonie
    Wen, K. Hoyan
    Widen, Elisabeth
    Yang, Qiong
    Zhao, Wei
    Adams, Hieab H. H.
    Arking, Dan E.
    Bilder, Robert M.
    Bitsios, Panos
    Boerwinkle, Eric
    Chiba-Falek, Ornit
    Corvin, Aiden
    De Jager, Philip L.
    Debette, Stephanie
    Donohoe, Gary
    Elliott, Paul
    Fitzpatrick, Annette L.
    Gill, Michael
    Glahn, David C.
    Hagg, Sara
    Hansell, Narelle K.
    Hariri, Ahmad R.
    Ikram, M. Kamran
    Jukema, J. Wouter
    Vuoksimaa, Eero
    Keller, Matthew C.
    Kremen, William S.
    Launer, Lenore
    Lindenberger, Ulman
    Palotie, Aarno
    Pedersen, Nancy L.
    Pendleton, Neil
    Porteous, David J.
    Raikkonen, Katri
    Raitakari, Olli T.
    Ramirez, Alfredo
    Reinvang, Ivar
    Rudan, Igor
    Rujescu, Dan
    Schmidt, Reinhold
    Schmidt, Helena
    Schofield, Peter W.
    Schofield, Peter R.
    Starr, John M.
    Steen, Vidar M.
    Trollor, Julian N.
    Turner, Steven T.
    Van Duijn, Cornelia M.
    Villringer, Arno
    Weinberger, Daniel R.
    Weir, David R.
    Wilson, James F.
    Malhotra, Anil
    McIntosh, Andrew M.
    Gale, Catharine R.
    Seshadri, Sudha
    Mosley, Thomas H., Jr.
    Bressler, Jan
    Lencz, Todd
    Deary, Ian J.
    Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2098Article in journal (Refereed)
    Abstract [en]

    General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

  • 41. de Frias, Cindy M
    et al.
    Annerbrink, Kristina
    Westberg, Lars
    Eriksson, Elias
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nilsson, Lars-Göran
    COMT gene polymorphism is associated with declarative memory in adulthood and old age2004In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 34, no 5, p. 533-539Article in journal (Refereed)
    Abstract [en]

    Variation in memory performance is to a large extent explained by genes. In the prefrontal cortex, the catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine, a neurotransmitter implicated in cognitive functions. The present study examined the effect of a polymorphism in the COMT gene on individual differences and changes in memory in adulthood and old age. Tests assessing episodic and semantic memory were administered to 286 men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula prospective cohort study) at two occasions followed over a 5-year period. Carriers of the Met/Met genotype (with low enzyme activity) performed better on episodic and semantic memory, as compared to carriers of the Val allele (with higher enzyme activity). Division of episodic memory into its recall and recognition components showed that the difference was specific to episodic recall, not recognition tasks; an effect that was observed across three age groups (middle-age, young-old, and old-old adults) and over a 5-year period. The COMT gene is a plausible candidate gene for memory functioning in adulthood and old age.

  • 42. Deng, Min
    et al.
    Wei, Ling
    Zuo, Xianbo
    Tian, Yanghua
    Xie, Fei
    Hu, Panpan
    Zhu, Chunyan
    Yu, Fengqiong
    Meng, Yu
    Wang, Honghao
    Zhang, Fangfang
    Ma, Huijuan
    Ye, Rong
    Cheng, Huaidong
    Du, Jing
    Dong, Wenwen
    Zhou, Shanshan
    Wang, Changqing
    Wang, Yu
    Wang, Jingye
    Chen, Xianwen
    Sun, Zhongwu
    Zhou, Nong
    Jiang, Yubao
    Liu, Xiuxiu
    Li, Xiaogang
    Zhang, Nan
    Liu, Na
    Guan, Yingjun
    Han, Yongsheng
    Han, Yongzhu
    Lv, Xinyi
    Fu, Yu
    Yu, Hui
    Xi, Chunhua
    Xie, Dandan
    Zhao, Qiyuan
    Xie, Peng
    Wang, Xin
    Zhang, Zhijun
    Shen, Lu
    Cui, Yong
    Yin, Xianyong
    Cheng, Hui
    Liang, Bo
    Zheng, Xiaodong
    Lee, Tatia M. C.
    Chen, Gang
    Zhou, Fusheng
    Veldink, Jan H.
    Robberecht, Wim
    Landers, John E.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Al-Chalabi, Ammar
    Shaw, Chris
    Liu, Chunfeng
    Tang, Beisha
    Xiao, Shangxi
    Robertson, Janice
    Zhang, Fengyu
    van den Berg, Leonard H.
    Sun, Liangdan
    Liu, Jianjun
    Yang, Sen
    Ju, Xiaodong
    Wang, Kai
    Zhang, Xuejun
    Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 6, p. 697-+Article in journal (Refereed)
    Abstract [en]

    To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, P-combined = 2.92 x 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, P-combined = 2.35 x 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.

  • 43. Descheemaeker, K.A.
    et al.
    Nelles, L
    Strandberg, L
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Collen, D
    Transfection of human endothelial cells with human plasminogen activator inhibitor type-1 promoter-reporter gene fragmentes reveals phorbol ester induciton of gene expression1992In: Fibrinolysis, ISSN 0268-9499, Vol. 6, no 4, p. 256-262Article in journal (Refereed)
  • 44. Dethoff, Elizabeth A
    et al.
    Petzold, Katja
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chugh, Jeetender
    Casiano-Negroni, Anette
    Al-Hashimi, Hashim M
    Visualizing transient low-populated structures of RNA2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7426, p. 724-728Article in journal (Refereed)
    Abstract [en]

    The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captured by structure characterization techniques. Here we report the nuclear magnetic resonance visualization of RNA transitions towards 'invisible' excited states (ESs), which exist in too little abundance (2-13%) and for too short a duration (45-250 μs) to allow structural characterization by conventional techniques. Transitions towards ESs result in localized rearrangements in base-pairing that alter building block elements of RNA architecture, including helix-junction-helix motifs and apical loops. The ES can inhibit function by sequestering residues involved in recognition and signalling or promote ATP-independent strand exchange. Thus, RNAs do not adopt a single conformation, but rather exist in rapid equilibrium with alternative ESs, which can be stabilized by cellular cues to affect functional outcomes.

  • 45.
    Djusberg, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lundberg, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases2017In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 6, p. 625-638Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

  • 46. Do, Ron
    et al.
    Willer, Cristen J.
    Schmidt, Ellen M.
    Sengupta, Sebanti
    Gao, Chi
    Peloso, Gina M.
    Gustafsson, Stefan
    Kanoni, Stavroula
    Ganna, Andrea
    Chen, Jin
    Buchkovich, Martin L.
    Mora, Samia
    Beckmann, Jacques S.
    Bragg-Gresham, Jennifer L.
    Chang, Hsing-Yi
    Demirkan, Ayse
    Den Hertog, Heleen M.
    Donnelly, Louise A.
    Ehret, Georg B.
    Esko, Tonu
    Feitosa, Mary F.
    Ferreira, Teresa
    Fischer, Krista
    Fontanillas, Pierre
    Fraser, Ross M.
    Freitag, Daniel F.
    Gurdasani, Deepti
    Heikkila, Kauko
    Hyppoenen, Elina
    Isaacs, Aaron
    Jackson, Anne U.
    Johansson, Asa
    Johnson, Toby
    Kaakinen, Marika
    Kettunen, Johannes
    Kleber, Marcus E.
    Li, Xiaohui
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    Magnusson, Patrik K. E.
    Mangino, Massimo
    Mihailov, Evelin
    Montasser, May E.
    Mueller-Nurasyid, Martina
    Nolte, Ilja M.
    O'Connell, Jeffrey R.
    Palmer, Cameron D.
    Perola, Markus
    Petersen, Ann-Kristin
    Sanna, Serena
    Saxena, Richa
    Service, Susan K.
    Shah, Sonia
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology. Lunds universitet.
    Sidore, Carlo
    Song, Ci
    Strawbridge, Rona J.
    Surakka, Ida
    Tanaka, Toshiko
    Teslovich, Tanya M.
    Thorleifsson, Gudmar
    Van den Herik, Evita G.
    Voight, Benjamin F.
    Volcik, Kelly A.
    Waite, Lindsay L.
    Wong, Andrew
    Wu, Ying
    Zhang, Weihua
    Absher, Devin
    Asiki, Gershim
    Barroso, Ines
    Been, Latonya F.
    Bolton, Jennifer L.
    Bonnycastle, Lori L.
    Brambilla, Paolo
    Burnett, Mary S.
    Cesana, Giancarlo
    Dimitriou, Maria
    Doney, Alex S. F.
    Doering, Angela
    Elliott, Paul
    Epstein, Stephen E.
    Eyjolfsson, Gudmundur Ingi
    Gigante, Bruna
    Goodarzi, Mark O.
    Grallert, Harald
    Gravito, Martha L.
    Groves, Christopher J.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Hernandez, Dena
    Hicks, Andrew A.
    Holm, Hilma
    Hung, Yi-Jen
    Illig, Thomas
    Jones, Michelle R.
    Kaleebu, Pontiano
    Kastelein, John J. P.
    Khaw, Kay-Tee
    Kim, Eric
    Klopp, Norman
    Komulainen, Pirjo
    Kumari, Meena
    Langenberg, Claudia
    Lehtimaki, Terho
    Lin, Shih-Yi
    Lindstrom, Jaana
    Loos, Ruth J. F.
    Mach, Francois
    McArdle, Wendy L.
    Meisinger, Christa
    Mitchell, Braxton D.
    Mueller, Gabrielle
    Nagaraja, Ramaiah
    Narisu, Narisu
    Nieminen, Tuomo V. M.
    Nsubuga, Rebecca N.
    Olafsson, Isleifur
    Ong, Ken K.
    Palotie, Aarno
    Papamarkou, Theodore
    Pomilla, Cristina
    Pouta, Anneli
    Rader, Daniel J.
    Reilly, Muredach P.
    Ridker, Paul M.
    Rivadeneira, Fernando
    Rudan, Igor
    Ruokonen, Aimo
    Samani, Nilesh
    Scharnagl, Hubert
    Seeley, Janet
    Silander, Kaisa
    Stancakova, Alena
    Stirrups, Kathleen
    Swift, Amy J.
    Tiret, Laurence
    Uitterlinden, Andre G.
    van Pelt, L. Joost
    Vedantam, Sailaja
    Wainwright, Nicholas
    Wijmenga, Cisca
    Wild, Sarah H.
    Willemsen, Gonneke
    Wilsgaard, Tom
    Wilson, James F.
    Young, Elizabeth H.
    Zhao, Jing Hua
    Adair, Linda S.
    Arveiler, Dominique
    Assimes, Themistocles L.
    Bandinelli, Stefania
    Bennett, Franklyn
    Bochud, Murielle
    Boehm, Bernhard O.
    Boomsma, Dorret I.
    Borecki, Ingrid B.
    Bornstein, Stefan R.
    Bovet, Pascal
    Burnier, Michel
    Campbell, Harry
    Chakravarti, Aravinda
    Chambers, John C.
    Chen, Yii-Der Ida
    Collins, Francis S.
    Cooper, Richard S.
    Danesh, John
    Dedoussis, George
    de Faire, Ulf
    Feranil, Alan B.
    Ferrieres, Jean
    Ferrucci, Luigi
    Freimer, Nelson B.
    Gieger, Christian
    Groop, Leif C.
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hamsten, Anders
    Harris, Tamara B.
    Hingorani, Aroon
    Hirschhorn, Joel N.
    Hofman, Albert
    Hovingh, G. Kees
    Hsiung, Chao Agnes
    Humphries, Steve E.
    Hunt, Steven C.
    Hveem, Kristian
    Iribarren, Carlos
    Jarvelin, Marjo-Riitta
    Jula, Antti
    Kahonen, Mika
    Kaprio, Jaakko
    Kesaniemi, Antero
    Kivimaki, Mika
    Kooner, Jaspal S.
    Koudstaal, Peter J.
    Krauss, Ronald M.
    Kuh, Diana
    Kuusisto, Johanna
    Kyvik, Kirsten O.
    Laakso, Markku
    Lakka, Timo A.
    Lind, Lars
    Lindgren, Cecilia M.
    Martin, Nicholas G.
    Maerz, Winfried
    McCarthy, Mark I.
    McKenzie, Colin A.
    Meneton, Pierre
    Metspalu, Andres
    Moilanen, Leena
    Morris, Andrew D.
    Munroe, Patricia B.
    Njolstad, Inger
    Pedersen, Nancy L.
    Power, Chris
    Pramstaller, Peter P.
    Price, Jackie F.
    Psaty, Bruce M.
    Quertermous, Thomas
    Rauramaa, Rainer
    Saleheen, Danish
    Salomaa, Veikko
    Sanghera, Dharambir K.
    Saramies, Jouko
    Schwarz, Peter E. H.
    Sheu, Wayne H-H
    Shuldiner, Alan R.
    Siegbahn, Agneta
    Spector, Tim D.
    Stefansson, Kari
    Strachan, David P.
    Tayo, Bamidele O.
    Tremoli, Elena
    Tuomilehto, Jaakko
    Uusitupa, Matti
    van Duijn, Cornelia M.
    Vollenweider, Peter
    Wallentin, Lars
    Wareham, Nicholas J.
    Whitfield, John B.
    Wolffenbuttel, Bruce H. R.
    Altshuler, David
    Ordovas, Jose M.
    Boerwinkle, Eric
    Palmer, Colin N. A.
    Thorsteinsdottir, Unnur
    Chasman, Daniel I.
    Rotter, Jerome I.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lunds universitet, Harvard University.
    Ripatti, Samuli
    Cupples, L. Adrienne
    Sandhu, Manjinder S.
    Rich, Stephen S.
    Boehnke, Michael
    Deloukas, Panos
    Mohlke, Karen L.
    Ingelsson, Erik
    Abecasis, Goncalo R.
    Daly, Mark J.
    Neale, Benjamin M.
    Kathiresan, Sekar
    Common variants associated with plasma triglycerides and risk for coronary artery disease2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 11, p. 1345-+Article in journal (Refereed)
    Abstract [en]

    Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

  • 47. Duell, Eric J
    et al.
    Lujan-Barroso, Leila
    Llivina, Claudia
    Muñoz, Xavier
    Jenab, Mazda
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Boeing, Heiner
    Buijsse, Brian
    Canzian, Federico
    Johnson, Theron
    Dalgård, Christine
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Sánchez, Soledad C
    Sánchez-Cantalejo, Emilio
    Huerta, José-María
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Travis, Ruth C
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Rafnsson, Snorri
    Palli, Domenico
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Grioni, Sara
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Numans, Mattijs E
    Peeters, Petra H
    Johansen, Dorthe
    Lindkvist, Björn
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Skeie, Guri
    Weiderpass, Elisabete
    Duarte-Salles, Talita
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Riboli, Elio
    Sala, Núria
    González, Carlos A
    Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort2013In: Genes & Nutrition, ISSN 1555-8932, E-ISSN 1865-3499, Vol. 8, no 6, p. 549-560Article in journal (Refereed)
    Abstract [en]

    Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.

  • 48. Dörr, Tobias
    et al.
    Lam, Hubert
    Alvarez, Laura
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Davis, Brigid M.
    Waldor, Matthew K.
    A novel peptidoglycan binding protein crucial for PBP1A-mediated cell wall biogenesis in Vibrio cholerae2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 6, p. e1004433-Article in journal (Refereed)
    Abstract [en]

    The bacterial cell wall, which is comprised of a mesh of polysaccharide strands crosslinked via peptide bridges (peptidoglycan, PG), is critical for maintenance of cell shape and survival. PG assembly is mediated by a variety of Penicillin Binding Proteins (PBP) whose fundamental activities have been characterized in great detail; however, there is limited knowledge of the factors that modulate their activities in different environments or growth phases. In Vibrio cholerae, the cause of cholera, PG synthesis during the transition into stationary phase is primarily mediated by the bifunctional enzyme PBP1A. Here, we screened an ordered V. cholerae transposon library for mutants that are sensitive to growth inhibition by non-canonical D-amino acids (DAA), which prevent growth and maintenance of cell shape in PBP1A-deficient V. cholerae. In addition to PBP1A and its lipoprotein activator LpoA, we found that CsiV, a small periplasmic protein with no previously described function, is essential for growth in the presence of DAA. Deletion of csiV, like deletion of lpoA or the PBP1A-encoding gene mrcA, causes cells to lose their rod shape in the presence of DAA or the beta-lactam antibiotic cefsulodin, and all three mutations are synthetically lethal with deletion of mrcB, which encodes PBP1B, V. cholerae's second key bifunctional PBP. CsiV interacts with LpoA and PG but apparently not with PBP1A, supporting the hypothesis that CsiV promotes LpoA's role as an activator of PBP1A, and thereby modulates V. cholerae PG biogenesis. Finally, the requirement for CsiV in PBP1A-mediated growth of V. cholerae can be overcome either by augmenting PG synthesis or by reducing PG degradation, thereby highlighting the importance of balancing these two processes for bacterial survival.

  • 49. Ehret, Georg B.
    et al.
    Ferreira, Teresa
    Chasman, Daniel I.
    Jackson, Anne U.
    Schmidt, Ellen M.
    Johnson, Toby
    Thorleifsson, Gudmar
    Luan, Jian'an
    Donnelly, Louise A.
    Kanoni, Stavroula
    Petersen, Ann -Kristin
    Pihurl, Vasyl
    Strawbridge, Rona J.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Odontology. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Hughes, Maria F.
    Meirelles, Osorio
    Kaakinen, Marika
    Bouatia-Naji, Nabila
    Kristiansson, Kati
    Shah, Sonia
    Kleber, Marcus E.
    Guo, Xiuqing
    Lyytikainen, Leo-Pekka
    Fava, Cristiano
    Eriksson, Nidas
    Nolte, Ilja M.
    Magnusson, Patrik K.
    Salfati, Elias L.
    Rallidis, Loukianos S.
    Theusch, Elizabeth
    Smith, Andrew J. P.
    Folkersen, Lasse
    Witkowska, Kate
    Pers, Tune H.
    Joehanes, Roby
    Kim, Stuart K.
    Lataniotis, Lazaros
    Jansen, Rick
    Johnson, Andrew D.
    Warren, Helen
    Kim, Young Jin
    Zhao, Wei
    Wu, Ying
    Tayo, Bamidele O.
    Bochud, Murielle
    Absher, Devin
    Adair, Linda S.
    Amin, Najaf
    Arkingl, Dan E.
    Axelsson, Tomas
    Baldassarre, Damian
    Balkau, Beverley
    Bandinelli, Stefania
    Barnes, Michael R.
    Barroso, Ines
    Bevan, Stephen
    Bis, Joshua C.
    Bjornsdottir, Gyda
    Boehnke, Michael
    Boerwinkle, Eric
    Bonnycastle, Lori L.
    Boomsma, Dorret I.
    Bornstein, Stefan R.
    Brown, Morris J.
    Burnier, Michel
    Cabrera, Claudia P.
    Chambers, John C.
    Chang, I-Shou
    Cheng, Ching-Yu
    Chines, Peter S.
    Chung, Ren-Hua
    Collins, Francis S.
    Connell, John M.
    Doring, Angela
    Dallongeville, Jean
    Danesh, John
    de Faire, Ulf
    Delgado, Graciela
    Dominiczak, Anna F.
    Doney, Alex S. F.
    Drenos, Fotios
    Edkins, Sarah
    Eicher, John D.
    Elosua, Roberto
    Enroth, Stefan
    Erdmann, Jeanette
    Eriksson, Per
    Esko, Tonu
    Evangelou, Evangelos
    Evans, Alun
    Fai, Tove
    Farra, Martin
    Felixl, Janine F.
    Ferrieres, Jean
    Ferrucci, Luigi
    Fornage, Myriam
    Forrester, Terrence
    Franceschinil, Nora
    Franco, Oscar H.
    Franco-Cereceda, Anders
    Fraser, Ross M.
    Ganesh, Santhi K.
    Gao, He
    Gertow, Karl
    Gianfagna, Francesco
    Gigante, Bruna
    Giulianini, Franco
    Goe, Anuj
    Goodall, Alison H.
    Goodarzi, Mark
    Gorski, Mathias
    Grassler, Jurgen
    Groves, Christopher J.
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hartikainen, Anna-Liisa
    Hassinen, Maija
    Havulinna, Aki S.
    Hayward, Caroline
    Hercberg, Serge
    Herzig, Karl-Heinz
    Hicks, Andrew A.
    Hingorani, Aroon D.
    Hirschhorn, Joel N.
    Hofmanl, Albert
    Holmen, Jostein
    Holmen, Oddgeir Lingaas
    Hottenga, Jouke-Jan
    Howard, Phil
    Hsiung, Chao A.
    Hunt, Steven C.
    Ikram, M. Arfan
    Illig, Thomas
    Iribarren, Carlos
    Jensen, Richard A.
    Kahonen, Mika
    Kang, Hyun Min
    Kathiresan, Sekar
    Keating, Brendan J.
    Khaw, Kay-Tee
    Kim, Yun Kyoung
    Kim, Eric
    Kivimaki, Mika
    Klopp, Norman
    Kolovou, Genovefa
    Komulainen, Pirjo
    Kooner, Jaspal S.
    Kosova, Gulum
    Krauss, Ronald M.
    Kuh, Diana
    Kutalik, Zoltan
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Lakka, Timo A.
    Lee, Nanette R.
    Lee, I-Te
    Lee, Wen-Jane
    Levy, Daniel
    Li, Xiaohui
    Liang, Kae-Woei
    Lin, Honghuang
    Lin, Li
    Lindstrom, Jaana
    Lobbens, Stephane
    Mannisto, Satu
    Muller, Gabriele
    Muller-Nurasyid, Martina
    Mach, Francois
    Markus, Hugh S.
    Marouli, Eirini
    McCarthy, Mark I.
    McKenzie, Colin A.
    Meneton, Pierre
    Menni, Cristina
    Metspalu, Andres
    Mijatovic, Vladan
    Moilanen, Leena
    Montasser, May E.
    Morris, Andrew D.
    Morrison, Alanna C.
    Mulas, Antonella
    Nagaraja, Ramaiah
    Narisu, Narisu
    Nikus, Kjell
    O'Donnell, Christopher J.
    O'Reilly, Paul F.
    Ong, Ken K.
    Paccaud, Fred
    Palmer, Cameron D.
    Parsa, Afshin
    Pedersen, Nancy L.
    Penninx, Brenda W.
    Perola, Markus
    Peters, Annette
    Poulter, Neil
    Pramstaller, Peter P.
    Psaty, Bruce M.
    Quertermous, Thomas
    Rao, Dabeeru C.
    Rasheed, Asif
    Rayner, N. William
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Rettig, Rainer
    Rice, Kenneth M.
    Roberts, Robert
    Rose, Lynda M.
    Rossouw, Jacques
    Samani, Nilesh J.
    Sanna, Serena
    Saramies, Jouko
    Schunkert, Heribert
    Sebert, Sylvain
    Sheu, Wayne H-H
    Shin, Young-Ah
    Sim, Xueling
    Smit, Johannes H.
    Smith, Albert V.
    Sosa, Maria X.
    Spector, Tim D.
    Stancakova, Alena
    Stanton, Alice V.
    Stirrups, Kathleen E.
    Stringham, Heather M.
    Sundstrom, Johan
    Swift, Amy J.
    Syvanen, Ann-Christine
    Tai, E-Shyong
    Tanaka, Toshiko
    Tarasov, Kirill V.
    Teumer, Alexander
    Thorsteinsdottir, Unnur
    Tobin, Martin D.
    Tremoli, Elena
    Uitterlinden, Andre G.
    Uusitupa, Matti
    Vaez, Ahmad
    Vaidya, Dhananjay
    van Duijn, Cornelia M.
    van Iperen, Erik P. A.
    Vasan, Ramachandran S.
    Verwoert, Germaine C.
    Virtamo, Jarmo
    Vitart, Veronique
    Voight, Benjamin F.
    Vollenweider, Peter
    Wagner, Aline
    Wain, Louise V.
    Wareham, Nicholas J.
    Watldns, Hugh
    Weder, Alan B.
    Westra, Harm Jan
    Wilks, Rainford
    Wilsgaard, Tom
    Wilson, James F.
    Wong, Tien Y.
    Yang, Tsun-Po
    Yao, Jie
    Yengo, Loic
    Zhang, Weihua
    Zhao, Jing Hua
    Zhu, Xiaofeng
    Bovet, Pascal
    Cooper, Richard S.
    Mohlke, Karen L.
    Saleheen, Danish
    Lee, Jong-Young
    Elliott, Paul
    Gierman, Hinco J.
    Willer, Cristen J.
    Franke, Lude
    Hovingh, G. Kees
    Taylor, Kent D.
    Dedoussis, George
    Sever, Peter
    Wong, Andrew
    Lind, Lars
    Assimes, Themistocles L.
    Njolstad, Inger
    Schwarz, Peter E. H.
    Langenberg, Claudia
    Snieder, Harold
    Caulfield, Mark J.
    Melander, E.
    Laakso, Markku
    Saltevo, Juha
    Rauramaa, Rainer
    Tuomilehto, Jaakko
    Ingelsson, Erik
    Lehtimaki, Terho
    Hveem, Kristian
    Palmas, Walter
    Marz, Winfried
    Kumar, Meena
    Salomaa, Veikko
    Chen, Yii-Der I.
    Rotter, Jerome I.
    Froguel, Philippe
    Jarvelin, Marjo-Riitta
    Lakatta, Edward G.
    Kuulasmaa, Kari
    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, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
    Hamsten, Anders
    Wichmann, H-Erich
    Palmer, Colin N. A.
    Stefansson, Kari
    Ridker, Paul M.
    Loos, Ruth J. F.
    Chalcravarti, Aravinda
    Deloukas, Panos
    Morris, Andrew P.
    Newton-Cheh, Christopher
    Munroe, Patricia B.
    The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 10, p. 1171-1184Article in journal (Refereed)
    Abstract [en]

    To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

  • 50.
    Einarsdottir, Elisabet
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Mapping genetic diseases in northern Sweden2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The population of northern Sweden has previously been shown to be well suited for the mapping of monogenic diseases. In this thesis we have tested the hypothesis that this population could also be used for efficient identification of risk genes for common diseases. In Paper I we have hypothesised that despite the admixture of Swedish, Finnish and Sami, the northern Swedish population consists of sub-populations geographically restricted by the main river valleys running through the region. This geographic isolation, in combination with founder effects and genetic drift, could represent a unique resource for genetic studies. On the other hand, it also underlines the importance of accounting for this e.g. in genetic association studies. To test this hypothesis, we studied the patterns of marriage within and between river valley regions and compared allelic frequencies of genetic markers between these regions. The tendency to find a spouse and live in the river valley where one was born is strong, and allelic frequencies of genetic markers vary significantly between adjacent regions. These data support our hypothesis that the river valleys are home to distinct sub-populations and that this is likely to affect mapping of genetic diseases in these populations. In Paper II, we tested the applicability of the population in mapping HSAN V, a monogenic disease. This disease was identified in only three consanguineous individuals suffering from a severe loss of deep pain perception and an impaired perception of heat. A genome-wide scan combined with sequencing of candidate genes resulted in the identification of a causative point mutation in the nerve growth factor beta (NGFB) gene. In Paper III, a large family with multiple members affected by familial forms of type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis (AITD) was studied. This syndrome was mapped to the IDDM12 region on 2q33, giving positive lodscores when conditioning on HLA haplotype. The linkage to HLA and to the IDDM12 region thus confirmed previous reports of linkage and/or association of T1DM and AITD to these loci and provided evidence that the same genetic factors may be mediating these diseases. This also supported the feasibility of mapping complex diseases in northern Sweden by the use of familial forms of these diseases. In Paper IV, we applied the same approach to study type 2 diabetes mellitus (T2DM). A non-parametric genome-wide scan was carried out on a family material from northern Sweden, and linkage was found to the calpain-10 locus, a previously described T2DM-susceptibility gene on 2q37. Together, these findings demonstrate that selecting for familial forms of even complex diseases, and choosing families from the same geographical region can efficiently reduce the genetic heterogeneity of the disease and facilitate the identification of risk genes for the disease.

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