@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} }