TY - JOUR T1 - Common genetic determinants of vitamin D insufficiency: a genome-wide association study. JF - Lancet Y1 - 2010 A1 - Wang, Thomas J A1 - Zhang, Feng A1 - Richards, J Brent A1 - Kestenbaum, Bryan A1 - van Meurs, Joyce B A1 - Berry, Diane A1 - Kiel, Douglas P A1 - Streeten, Elizabeth A A1 - Ohlsson, Claes A1 - Koller, Daniel L A1 - Peltonen, Leena A1 - Cooper, Jason D A1 - O'Reilly, Paul F A1 - Houston, Denise K A1 - Glazer, Nicole L A1 - Vandenput, Liesbeth A1 - Peacock, Munro A1 - Shi, Julia A1 - Rivadeneira, Fernando A1 - McCarthy, Mark I A1 - Anneli, Pouta A1 - de Boer, Ian H A1 - Mangino, Massimo A1 - Kato, Bernet A1 - Smyth, Deborah J A1 - Booth, Sarah L A1 - Jacques, Paul F A1 - Burke, Greg L A1 - Goodarzi, Mark A1 - Cheung, Ching-Lung A1 - Wolf, Myles A1 - Rice, Kenneth A1 - Goltzman, David A1 - Hidiroglou, Nick A1 - Ladouceur, Martin A1 - Wareham, Nicholas J A1 - Hocking, Lynne J A1 - Hart, Deborah A1 - Arden, Nigel K A1 - Cooper, Cyrus A1 - Malik, Suneil A1 - Fraser, William D A1 - Hartikainen, Anna-Liisa A1 - Zhai, Guangju A1 - Macdonald, Helen M A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Reid, David M A1 - Hakim, Alan A1 - Dennison, Elaine A1 - Liu, Yongmei A1 - Power, Chris A1 - Stevens, Helen E A1 - Jaana, Laitinen A1 - Vasan, Ramachandran S A1 - Soranzo, Nicole A1 - Bojunga, Jörg A1 - Psaty, Bruce M A1 - Lorentzon, Mattias A1 - Foroud, Tatiana A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Jansson, John-Olov A1 - Cauley, Jane A A1 - Uitterlinden, André G A1 - Gibson, Quince A1 - Jarvelin, Marjo-Riitta A1 - Karasik, David A1 - Siscovick, David S A1 - Econs, Michael J A1 - Kritchevsky, Stephen B A1 - Florez, Jose C A1 - Todd, John A A1 - Dupuis, Josée A1 - Hyppönen, Elina A1 - Spector, Timothy D KW - Canada KW - Chromosomes, Human, Pair 11 KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - Dietary Supplements KW - Europe KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heterozygote KW - Homozygote KW - Humans KW - Immunoassay KW - International Cooperation KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide KW - Seasons KW - United States KW - Vitamin D KW - Vitamin D Deficiency AB -

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

VL - 376 IS - 9736 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20541252?dopt=Abstract ER - TY - JOUR T1 - Assessment of gene-by-sex interaction effect on bone mineral density. JF - J Bone Miner Res Y1 - 2012 A1 - Liu, Ching-Ti A1 - Estrada, Karol A1 - Yerges-Armstrong, Laura M A1 - Amin, Najaf A1 - Evangelou, Evangelos A1 - Li, Guo A1 - Minster, Ryan L A1 - Carless, Melanie A A1 - Kammerer, Candace M A1 - Oei, Ling A1 - Zhou, Yanhua A1 - Alonso, Nerea A1 - Dailiana, Zoe A1 - Eriksson, Joel A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Husted, Lise Bjerre A1 - Khusainova, Rita I A1 - Koromila, Theodora A1 - Kung, Annie Waichee A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Richards, J Brent A1 - Sham, Pak Chung A1 - Spector, Timothy A1 - Vandenput, Liesbeth A1 - Xiao, Su-Mei A1 - Zheng, Hou-Feng A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza K A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Marc, Janja A1 - Mellström, Dan A1 - Ohlsson, Claes A1 - Olmos, José M A1 - Ralston, Stuart H A1 - Riancho, José A A1 - Rousseau, François A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Zarrabeitia, María T A1 - Castano-Betancourt, Martha A1 - Demissie, Serkalem A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Kwan, Tony A1 - Medina-Gómez, Carolina A1 - Pastinen, Tomi A1 - Sigurdsson, Gunnar A1 - Thorleifsson, Gudmar A1 - Vanmeurs, Joyce Bj A1 - Blangero, John A1 - Hofman, Albert A1 - Liu, Yongmei A1 - Mitchell, Braxton D A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Rotter, Jerome I A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Thorsteinsdottir, Unnur A1 - Tylavsky, Frances A A1 - Uitterlinden, Andre A1 - Cauley, Jane A A1 - Harris, Tamara B A1 - Ioannidis, John Pa A1 - Psaty, Bruce M A1 - Robbins, John A A1 - Zillikens, M Carola A1 - Vanduijn, Cornelia M A1 - Prince, Richard L A1 - Karasik, David A1 - Rivadeneira, Fernando A1 - Kiel, Douglas P A1 - Cupples, L Adrienne A1 - Hsu, Yi-Hsiang KW - Bone Density KW - Cohort Studies KW - Female KW - Genes KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results KW - Sex Characteristics AB -

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.

VL - 27 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22692763?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. JF - Nat Genet Y1 - 2012 A1 - Estrada, Karol A1 - Styrkarsdottir, Unnur A1 - Evangelou, Evangelos A1 - Hsu, Yi-Hsiang A1 - Duncan, Emma L A1 - Ntzani, Evangelia E A1 - Oei, Ling A1 - Albagha, Omar M E A1 - Amin, Najaf A1 - Kemp, John P A1 - Koller, Daniel L A1 - Li, Guo A1 - Liu, Ching-Ti A1 - Minster, Ryan L A1 - Moayyeri, Alireza A1 - Vandenput, Liesbeth A1 - Willner, Dana A1 - Xiao, Su-Mei A1 - Yerges-Armstrong, Laura M A1 - Zheng, Hou-Feng A1 - Alonso, Nerea A1 - Eriksson, Joel A1 - Kammerer, Candace M A1 - Kaptoge, Stephen K A1 - Leo, Paul J A1 - Thorleifsson, Gudmar A1 - Wilson, Scott G A1 - Wilson, James F A1 - Aalto, Ville A1 - Alen, Markku A1 - Aragaki, Aaron K A1 - Aspelund, Thor A1 - Center, Jacqueline R A1 - Dailiana, Zoe A1 - Duggan, David J A1 - Garcia, Melissa A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Hallmans, Göran A1 - Hocking, Lynne J A1 - Husted, Lise Bjerre A1 - Jameson, Karen A A1 - Khusainova, Rita A1 - Kim, Ghi Su A1 - Kooperberg, Charles A1 - Koromila, Theodora A1 - Kruk, Marcin A1 - Laaksonen, Marika A1 - LaCroix, Andrea Z A1 - Lee, Seung Hun A1 - Leung, Ping C A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nguyen, Tuan V A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Rose, Lynda M A1 - Scollen, Serena A1 - Siggeirsdottir, Kristin A1 - Smith, Albert V A1 - Svensson, Olle A1 - Trompet, Stella A1 - Trummer, Olivia A1 - van Schoor, Natasja M A1 - Woo, Jean A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Buckley, Brendan M A1 - Cheng, Sulin A1 - Christiansen, Claus A1 - Cooper, Cyrus A1 - Dedoussis, George A1 - Ford, Ian A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Kähönen, Mika A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza A1 - Koh, Jung-Min A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Leslie, William D A1 - Lips, Paul A1 - Ljunggren, Osten A1 - Lorenc, Roman S A1 - Marc, Janja A1 - Mellström, Dan A1 - Obermayer-Pietsch, Barbara A1 - Olmos, José M A1 - Pettersson-Kymmer, Ulrika A1 - Reid, David M A1 - Riancho, José A A1 - Ridker, Paul M A1 - Rousseau, François A1 - Slagboom, P Eline A1 - Tang, Nelson L S A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Viikari, Jorma A1 - Zarrabeitia, María T A1 - Aulchenko, Yurii S A1 - Castano-Betancourt, Martha A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Ingvarsson, Thorvaldur A1 - Johannsdottir, Hrefna A1 - Kwan, Tony A1 - Li, Rui A1 - Luben, Robert A1 - Medina-Gómez, Carolina A1 - Palsson, Stefan Th A1 - Reppe, Sjur A1 - Rotter, Jerome I A1 - Sigurdsson, Gunnar A1 - van Meurs, Joyce B J A1 - Verlaan, Dominique A1 - Williams, Frances M K A1 - Wood, Andrew R A1 - Zhou, Yanhua A1 - Gautvik, Kaare M A1 - Pastinen, Tomi A1 - Raychaudhuri, Soumya A1 - Cauley, Jane A A1 - Chasman, Daniel I A1 - Clark, Graeme R A1 - Cummings, Steven R A1 - Danoy, Patrick A1 - Dennison, Elaine M A1 - Eastell, Richard A1 - Eisman, John A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Jackson, Rebecca D A1 - Jones, Graeme A1 - Jukema, J Wouter A1 - Khaw, Kay-Tee A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Lorentzon, Mattias A1 - McCloskey, Eugene A1 - Mitchell, Braxton D A1 - Nandakumar, Kannabiran A1 - Nicholson, Geoffrey C A1 - Oostra, Ben A A1 - Peacock, Munro A1 - Pols, Huibert A P A1 - Prince, Richard L A1 - Raitakari, Olli A1 - Reid, Ian R A1 - Robbins, John A1 - Sambrook, Philip N A1 - Sham, Pak Chung A1 - Shuldiner, Alan R A1 - Tylavsky, Frances A A1 - van Duijn, Cornelia M A1 - Wareham, Nick J A1 - Cupples, L Adrienne A1 - Econs, Michael J A1 - Evans, David M A1 - Harris, Tamara B A1 - Kung, Annie Wai Chee A1 - Psaty, Bruce M A1 - Reeve, Jonathan A1 - Spector, Timothy D A1 - Streeten, Elizabeth A A1 - Zillikens, M Carola A1 - Thorsteinsdottir, Unnur A1 - Ohlsson, Claes A1 - Karasik, David A1 - Richards, J Brent A1 - Brown, Matthew A A1 - Stefansson, Kari A1 - Uitterlinden, André G A1 - Ralston, Stuart H A1 - Ioannidis, John P A A1 - Kiel, Douglas P A1 - Rivadeneira, Fernando KW - Bone Density KW - Computational Biology KW - European Continental Ancestry Group KW - Extracellular Matrix Proteins KW - Female KW - Femur Neck KW - Fractures, Bone KW - Gene Expression Profiling KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Glycoproteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-5 KW - Lumbar Vertebrae KW - Male KW - Mitochondrial Membrane Transport Proteins KW - Osteoporosis KW - Phosphoproteins KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Spectrin AB -

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

VL - 44 IS - 5 ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gérard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Polymerase gamma KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. JF - Nat Commun Y1 - 2017 A1 - Zillikens, M Carola A1 - Demissie, Serkalem A1 - Hsu, Yi-Hsiang A1 - Yerges-Armstrong, Laura M A1 - Chou, Wen-Chi A1 - Stolk, Lisette A1 - Livshits, Gregory A1 - Broer, Linda A1 - Johnson, Toby A1 - Koller, Daniel L A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Malkin, Ida A1 - Ried, Janina S A1 - Smith, Albert V A1 - Thorleifsson, Gudmar A1 - Vandenput, Liesbeth A1 - Hua Zhao, Jing A1 - Zhang, Weihua A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Baier, Leslie J A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Biffar, Rainer A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos Obanda, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Cederberg, Henna A1 - Chen, Zhao A1 - Cho, Nam H A1 - Jin Choi, Hyung A1 - Claussnitzer, Melina A1 - Collins, Francis A1 - Cummings, Steven R A1 - De Jager, Philip L A1 - Demuth, Ilja A1 - Dhonukshe-Rutten, Rosalie A M A1 - Diatchenko, Luda A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Erdos, Mike A1 - Eriksson, Johan G A1 - Eriksson, Joel A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Girke, Thomas A1 - Glazer, Nicole L A1 - Grallert, Harald A1 - Grewal, Jagvir A1 - Han, Bok-Ghee A1 - Hanson, Robert L A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Hoffman, Eric P A1 - Homuth, Georg A1 - Hsueh, Wen-Chi A1 - Hubal, Monica J A1 - Hubbard, Alan A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koistinen, Heikki A A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Launer, Lenore J A1 - Lee, Jong-Young A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Liu, Tian A1 - Liu, Youfang A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Maixner, William A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Melov, Simon A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Newman, Anne A1 - Nielson, Carrie M A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Parker, Stephen C J A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Prince, Richard L A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schadt, Eric E A1 - Schipf, Sabine A1 - Scott, Laura A1 - Sehmi, Joban A1 - Shen, Jian A1 - Soo Shin, Chan A1 - Sigurdsson, Gunnar A1 - Smith, Shad A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Steinhagen-Thiessen, Elisabeth A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Tan, Sian-Tsung A1 - Tarnopolsky, Mark A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Tuomilehto, Jaakko A1 - van Schoor, Natasja M A1 - Verma, Arjun A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - Weedon, Michael N A1 - Welch, Ryan A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Xie, Weijia A1 - Yu, Lei A1 - Zhou, Yanhua A1 - Chambers, John C A1 - Döring, Angela A1 - van Duijn, Cornelia M A1 - Econs, Michael J A1 - Gudnason, Vilmundur A1 - Kooner, Jaspal S A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Ossowski, Vicky A1 - Waterworth, Dawn A1 - Loos, Ruth J F A1 - Karasik, David A1 - Harris, Tamara B A1 - Ohlsson, Claes A1 - Kiel, Douglas P AB -

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

VL - 8 IS - 1 ER - TY - JOUR T1 - Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. JF - Nat Commun Y1 - 2018 A1 - Jiang, Xia A1 - O'Reilly, Paul F A1 - Aschard, Hugues A1 - Hsu, Yi-Hsiang A1 - Richards, J Brent A1 - Dupuis, Josée A1 - Ingelsson, Erik A1 - Karasik, David A1 - Pilz, Stefan A1 - Berry, Diane A1 - Kestenbaum, Bryan A1 - Zheng, Jusheng A1 - Luan, Jianan A1 - Sofianopoulou, Eleni A1 - Streeten, Elizabeth A A1 - Albanes, Demetrius A1 - Lutsey, Pamela L A1 - Yao, Lu A1 - Tang, Weihong A1 - Econs, Michael J A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Zhou, Ang A1 - Power, Chris A1 - McCarthy, Mark I A1 - Michos, Erin D A1 - Boerwinkle, Eric A1 - Weinstein, Stephanie J A1 - Freedman, Neal D A1 - Huang, Wen-Yi A1 - van Schoor, Natasja M A1 - van der Velde, Nathalie A1 - Groot, Lisette C P G M de A1 - Enneman, Anke A1 - Cupples, L Adrienne A1 - Booth, Sarah L A1 - Vasan, Ramachandran S A1 - Liu, Ching-Ti A1 - Zhou, Yanhua A1 - Ripatti, Samuli A1 - Ohlsson, Claes A1 - Vandenput, Liesbeth A1 - Lorentzon, Mattias A1 - Eriksson, Johan G A1 - Shea, M Kyla A1 - Houston, Denise K A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Ferrucci, Luigi A1 - Peacock, Munro A1 - Gieger, Christian A1 - Beekman, Marian A1 - Slagboom, Eline A1 - Deelen, Joris A1 - Heemst, Diana van A1 - Kleber, Marcus E A1 - März, Winfried A1 - de Boer, Ian H A1 - Wood, Alexis C A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Robinson-Cohen, Cassianne A1 - den Heijer, Martin A1 - Jarvelin, Marjo-Riitta A1 - Cavadino, Alana A1 - Joshi, Peter K A1 - Wilson, James F A1 - Hayward, Caroline A1 - Lind, Lars A1 - Michaëlsson, Karl A1 - Trompet, Stella A1 - Zillikens, M Carola A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Broer, Linda A1 - Zgaga, Lina A1 - Campbell, Harry A1 - Theodoratou, Evropi A1 - Farrington, Susan M A1 - Timofeeva, Maria A1 - Dunlop, Malcolm G A1 - Valdes, Ana M A1 - Tikkanen, Emmi A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Raitakari, Olli T A1 - Mikkilä, Vera A1 - Ikram, M Arfan A1 - Sattar, Naveed A1 - Jukema, J Wouter A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Forouhi, Nita G A1 - Gundersen, Thomas E A1 - Khaw, Kay-Tee A1 - Butterworth, Adam S A1 - Danesh, John A1 - Spector, Timothy A1 - Wang, Thomas J A1 - Hyppönen, Elina A1 - Kraft, Peter A1 - Kiel, Douglas P AB -

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

VL - 9 IS - 1 ER - TY - JOUR T1 - Disentangling the genetics of lean mass. JF - Am J Clin Nutr Y1 - 2019 A1 - Karasik, David A1 - Zillikens, M Carola A1 - Hsu, Yi-Hsiang A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Bochud, Murielle A1 - Borecki, Ingrid B A1 - Broer, Linda A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos-Obando, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Chambers, John C A1 - Chen, Zhao A1 - Cho, Nam H A1 - Choi, Hyung Jin A1 - Chou, Wen-Chi A1 - Cummings, Steven R A1 - de Groot, Lisette C P G M A1 - De Jager, Phillip L A1 - Demuth, Ilja A1 - Diatchenko, Luda A1 - Econs, Michael J A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Eriksson, Joel A1 - Eriksson, Johan G A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Gieger, Christian A1 - Grallert, Harald A1 - Gudnason, Vilmundur A1 - Lenore, Launer J A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Homuth, Georg A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Johnson, Toby A1 - Biffar, Reiner A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koller, Daniel L A1 - Kooner, Jaspal S A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kutalik, Zoltán A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lill, Christina A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Livshits, Gregory A1 - Ljunggren, Osten A1 - Loos, Ruth J F A1 - Lorentzon, Mattias A1 - Luan, Jian'an A1 - Luben, Robert N A1 - Malkin, Ida A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Nethander, Maria A1 - Newman, Anne B A1 - O'Connell, Jeffery R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Prince, Richard L A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schipf, Sabine A1 - Shin, Chan Soo A1 - Smith, Albert V A1 - Smith, Shad B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stančáková, Alena A1 - Stefansson, Kari A1 - Steinhagen-Thiessen, Elisabeth A1 - Stolk, Lisette A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - van Schoor, Natasja M A1 - Vandenput, Liesbeth A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - J Wareham, Nicholas A1 - Waterworth, Dawn A1 - Weedon, Michael N A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Yerges-Armstrong, Laura M A1 - Yu, Lei A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Zhou, Yanhua A1 - Nielson, Carrie M A1 - Harris, Tamara B A1 - Demissie, Serkalem A1 - Kiel, Douglas P A1 - Ohlsson, Claes AB -

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

VL - 109 IS - 2 ER -