@article {1204, title = {Common genetic determinants of vitamin D insufficiency: a genome-wide association study.}, journal = {Lancet}, volume = {376}, year = {2010}, month = {2010 Jul 17}, pages = {180-8}, abstract = {

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).

}, keywords = {Canada, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 4, Cohort Studies, Dietary Supplements, Europe, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Homozygote, Humans, Immunoassay, International Cooperation, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Seasons, United States, Vitamin D, Vitamin D Deficiency}, issn = {1474-547X}, doi = {10.1016/S0140-6736(10)60588-0}, author = {Wang, Thomas J and Zhang, Feng and Richards, J Brent and Kestenbaum, Bryan and van Meurs, Joyce B and Berry, Diane and Kiel, Douglas P and Streeten, Elizabeth A and Ohlsson, Claes and Koller, Daniel L and Peltonen, Leena and Cooper, Jason D and O{\textquoteright}Reilly, Paul F and Houston, Denise K and Glazer, Nicole L and Vandenput, Liesbeth and Peacock, Munro and Shi, Julia and Rivadeneira, Fernando and McCarthy, Mark I and Anneli, Pouta and de Boer, Ian H and Mangino, Massimo and Kato, Bernet and Smyth, Deborah J and Booth, Sarah L and Jacques, Paul F and Burke, Greg L and Goodarzi, Mark and Cheung, Ching-Lung and Wolf, Myles and Rice, Kenneth and Goltzman, David and Hidiroglou, Nick and Ladouceur, Martin and Wareham, Nicholas J and Hocking, Lynne J and Hart, Deborah and Arden, Nigel K and Cooper, Cyrus and Malik, Suneil and Fraser, William D and Hartikainen, Anna-Liisa and Zhai, Guangju and Macdonald, Helen M and Forouhi, Nita G and Loos, Ruth J F and Reid, David M and Hakim, Alan and Dennison, Elaine and Liu, Yongmei and Power, Chris and Stevens, Helen E and Jaana, Laitinen and Vasan, Ramachandran S and Soranzo, Nicole and Bojunga, J{\"o}rg and Psaty, Bruce M and Lorentzon, Mattias and Foroud, Tatiana and Harris, Tamara B and Hofman, Albert and Jansson, John-Olov and Cauley, Jane A and Uitterlinden, Andr{\'e} G and Gibson, Quince and Jarvelin, Marjo-Riitta and Karasik, David and Siscovick, David S and Econs, Michael J and Kritchevsky, Stephen B and Florez, Jose C and Todd, John A and Dupuis, Jos{\'e}e and Hypp{\"o}nen, Elina and Spector, Timothy D} } @article {8016, title = {Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 15}, pages = {491-501}, abstract = {

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 {\texttimes} 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 {\texttimes} 10(-4), Bonferroni corrected), of which six reached P < 5 {\texttimes} 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.

}, keywords = {Bone Density, Computational Biology, European Continental Ancestry Group, Extracellular Matrix Proteins, Female, Femur Neck, Fractures, Bone, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-5, Lumbar Vertebrae, Male, Mitochondrial Membrane Transport Proteins, Osteoporosis, Phosphoproteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Spectrin}, issn = {1546-1718}, doi = {10.1038/ng.2249}, author = {Estrada, Karol and Styrkarsdottir, Unnur and Evangelou, Evangelos and Hsu, Yi-Hsiang and Duncan, Emma L and Ntzani, Evangelia E and Oei, Ling and Albagha, Omar M E and Amin, Najaf and Kemp, John P and Koller, Daniel L and Li, Guo and Liu, Ching-Ti and Minster, Ryan L and Moayyeri, Alireza and Vandenput, Liesbeth and Willner, Dana and Xiao, Su-Mei and Yerges-Armstrong, Laura M and Zheng, Hou-Feng and Alonso, Nerea and Eriksson, Joel and Kammerer, Candace M and Kaptoge, Stephen K and Leo, Paul J and Thorleifsson, Gudmar and Wilson, Scott G and Wilson, James F and Aalto, Ville and Alen, Markku and Aragaki, Aaron K and Aspelund, Thor and Center, Jacqueline R and Dailiana, Zoe and Duggan, David J and Garcia, Melissa and Garc{\'\i}a-Giralt, Natalia and Giroux, Sylvie and Hallmans, G{\"o}ran and Hocking, Lynne J and Husted, Lise Bjerre and Jameson, Karen A and Khusainova, Rita and Kim, Ghi Su and Kooperberg, Charles and Koromila, Theodora and Kruk, Marcin and Laaksonen, Marika and LaCroix, Andrea Z and Lee, Seung Hun and Leung, Ping C and Lewis, Joshua R and Masi, Laura and Mencej-Bedrac, Simona and Nguyen, Tuan V and Nogues, Xavier and Patel, Millan S and Prezelj, Janez and Rose, Lynda M and Scollen, Serena and Siggeirsdottir, Kristin and Smith, Albert V and Svensson, Olle and Trompet, Stella and Trummer, Olivia and van Schoor, Natasja M and Woo, Jean and Zhu, Kun and Balcells, Susana and Brandi, Maria Luisa and Buckley, Brendan M and Cheng, Sulin and Christiansen, Claus and Cooper, Cyrus and Dedoussis, George and Ford, Ian and Frost, Morten and Goltzman, David and Gonz{\'a}lez-Mac{\'\i}as, Jes{\'u}s and K{\"a}h{\"o}nen, Mika and Karlsson, Magnus and Khusnutdinova, Elza and Koh, Jung-Min and Kollia, Panagoula and Langdahl, Bente Lomholt and Leslie, William D and Lips, Paul and Ljunggren, Osten and Lorenc, Roman S and Marc, Janja and Mellstr{\"o}m, Dan and Obermayer-Pietsch, Barbara and Olmos, Jos{\'e} M and Pettersson-Kymmer, Ulrika and Reid, David M and Riancho, Jos{\'e} A and Ridker, Paul M and Rousseau, Fran{\c c}ois and Slagboom, P Eline and Tang, Nelson L S and Urreizti, Roser and Van Hul, Wim and Viikari, Jorma and Zarrabeitia, Mar{\'\i}a T and Aulchenko, Yurii S and Castano-Betancourt, Martha and Grundberg, Elin and Herrera, Lizbeth and Ingvarsson, Thorvaldur and Johannsdottir, Hrefna and Kwan, Tony and Li, Rui and Luben, Robert and Medina-G{\'o}mez, Carolina and Palsson, Stefan Th and Reppe, Sjur and Rotter, Jerome I and Sigurdsson, Gunnar and van Meurs, Joyce B J and Verlaan, Dominique and Williams, Frances M K and Wood, Andrew R and Zhou, Yanhua and Gautvik, Kaare M and Pastinen, Tomi and Raychaudhuri, Soumya and Cauley, Jane A and Chasman, Daniel I and Clark, Graeme R and Cummings, Steven R and Danoy, Patrick and Dennison, Elaine M and Eastell, Richard and Eisman, John A and Gudnason, Vilmundur and Hofman, Albert and Jackson, Rebecca D and Jones, Graeme and Jukema, J Wouter and Khaw, Kay-Tee and Lehtim{\"a}ki, Terho and Liu, Yongmei and Lorentzon, Mattias and McCloskey, Eugene and Mitchell, Braxton D and Nandakumar, Kannabiran and Nicholson, Geoffrey C and Oostra, Ben A and Peacock, Munro and Pols, Huibert A P and Prince, Richard L and Raitakari, Olli and Reid, Ian R and Robbins, John and Sambrook, Philip N and Sham, Pak Chung and Shuldiner, Alan R and Tylavsky, Frances A and van Duijn, Cornelia M and Wareham, Nick J and Cupples, L Adrienne and Econs, Michael J and Evans, David M and Harris, Tamara B and Kung, Annie Wai Chee and Psaty, Bruce M and Reeve, Jonathan and Spector, Timothy D and Streeten, Elizabeth A and Zillikens, M Carola and Thorsteinsdottir, Unnur and Ohlsson, Claes and Karasik, David and Richards, J Brent and Brown, Matthew A and Stefansson, Kari and Uitterlinden, Andr{\'e} G and Ralston, Stuart H and Ioannidis, John P A and Kiel, Douglas P and Rivadeneira, Fernando} }