Author
WANG, THOMAS - Massachusetts General Hospital | |
FENG, ZHANG - King'S College | |
RICHARDS, BRENT - McGill University - Canada | |
KESTENBAUM, BRYAN - University Of Washington Medical School | |
VAN MEURS, JOYCE - Erasmus Medical Center | |
BERRY, DIANE - University College Medical School - London | |
KIEL, DOUGLAS - Harvard Medical School | |
STREETEN, ELIZABETH - University Of Maryland | |
OHLSSON, CLAES - University Of Goteborg | |
KOLLER, DANIEL - Indiana University School Of Medicine | |
JARVELIN, MARJO-RIITTA - Imperial College Of Medicine | |
COOPER, JASON - University Of Cambridge | |
O'REILLY, PAUL - Imperial College Of Medicine | |
HOUSTON, DENISE - Wake Forest School Of Medicine | |
GLAZER, NICOLE - University Of Washington Medical School | |
VANDENPUT, LIESBETH - University Of Goteborg | |
PEACOCK, MUNRO - Indiana University School Of Medicine | |
SHI, JULIA - University Of Maryland | |
RIVADENEIRA, FERNANDO - Erasmus Medical Center | |
MCCARTHY, MARK - Oxford University | |
ANNELI, POUTA - University Of Oulu | |
DE BOER, IAN - University Of Washington Medical School | |
MANGINO, MASSIMO - King'S College | |
KATO, BERNET - King'S College | |
SMYTH, DEBORAH - University Of Cambridge | |
BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University | |
JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University | |
BURKE, GREG - Wake Forest University | |
GOODARZI, MARK - Cedars-Sinai Medical Center | |
CHEUNG, CHING-LUNG - Hebrew Seniorlife Research | |
WOLF, MYLES - University Of Miami | |
RICE, KENNETH - University Of Washington Medical School | |
GOLTZMAN, DAVID - McGill University - Canada | |
HIDIROGLOU, NICK - Health Canada | |
LADOUCEUR, MARTIN - McGill University - Canada | |
HUI, SIU - Indiana University School Of Medicine | |
WAREHAM, NICHOLAS - Mrc Human Nutrition Research | |
HOCKING, LYNNE - University Of Aberdeen | |
HART, DEBORAH - King'S College | |
ARDEN, NIGEL - University Of Southampton | |
COPPER, CYRUS - University Of Southampton | |
MALIK, SUNEIL - Public Health Agency Of Canada | |
FRASER, WILLIAM - University Of Liverpool | |
HARTIKAINEN, ANNA-LISA - University Of Oulu | |
ZHAI, GUANGJU - Luiz De Queiroz College Of Agriculture (ESALQ) | |
MACDONALD, HELEN - University Of Aberdeen | |
FOROUHI, NITA - Mrc Human Nutrition Research | |
LOOS, RUTH - Mrc Human Nutrition Research | |
REID, DAVID - University Of Aberdeen | |
HAKIM, ALAN - Whipps Cross University Hosptial | |
DENNISON, ELAINE - University Of Southampton | |
LIU, YONGMEI - Wake Forest School Of Medicine | |
POWER, CHRIS - University College Medical School - London | |
STEVENS, HELEN - University Of Cambridge | |
JAANA, LAITINEN - University Of Oulu | |
VASAN, RAMACHANDRAN - Framingham Heart Study | |
SORANZO, NICOLE - King'S College | |
BOJUNGA, JOERG - Frankfurt University | |
PSTAY, BRUCE - University Of Washington Medical School | |
LORENTZON, MATTIAS - University Of Goteborg | |
FOROUD, TATIANA - Indiana University School Of Medicine | |
HARRIS, TAMARA - National Institutes Of Health (NIH) | |
HOFMAN, ALBERT - Netherlands Genomics Initiative | |
JANSSON, JOHN-OLOV - University Of Goteborg | |
CAULEY, JANE - University Of Pittsburgh | |
UITTERLINDEN, ANDRE - Netherlands Genomics Initiative | |
GIBSON, QUINCE - Erasmus Medical Center | |
PALOTIE, LEENA - Wellcome Trust Sanger Institute | |
KARASIK, DAVID - Harvard Medical School | |
ECONS, MICHAEL - Indiana University School Of Medicine | |
KRITCHEVSKY, STEPHEN - Wake Forest School Of Medicine | |
FLOREZ, JOSE - Harvard Medical School | |
TODD, JOHN - University Of Cambridge | |
DUPUIS, JOSEE - Framingham Heart Study | |
HYPPONEN, ELINA - University College Medical School - London | |
SPECTOR, TIMOTHY - King'S College |
Submitted to: Lancet
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 3/1/2010 Publication Date: 7/20/2010 Citation: Wang, T.J., Feng, Z., Richards, B., Kestenbaum, B., Van Meurs, J.B., Berry, D., Kiel, D., Streeten, E.A., Ohlsson, C., Koller, D.L., Jarvelin, M., Cooper, J.D., O'Reilly, P.F., Houston, D.K., Glazer, N.L., Vandenput, L., Peacock, M., Shi, J., Rivadeneira, F., Mccarthy, M.I., Anneli, P., De Boer, I.H., Mangino, M., Kato, B., Smyth, D.J., Booth, S.L., Jacques, P.F., Burke, G.L., Goodarzi, M., Cheung, C., Wolf, M., Rice, K., Goltzman, D., Hidiroglou, N., Ladouceur, M., Hui, S.L., Wareham, N.J., Hocking, L.J., Hart, D., Arden, N.K., Copper, C., Malik, S., Fraser, W.D., Hartikainen, A., Zhai, G., Macdonald, H., Forouhi, N.G., Loos, R.J., Reid, D.M., Hakim, A., Dennison, E., Liu, Y., Power, C., Stevens, H.E., Jaana, L., Vasan, R.S., Soranzo, N., Bojunga, J., Pstay, B.M., Lorentzon, M., Foroud, T., Harris, T.B., Hofman, A., Jansson, J., Cauley, J.A., Uitterlinden, A.G., Gibson, Q., Palotie, L., Karasik, D.S., Econs, M.J., Kritchevsky, S.B., Florez, J.C., Todd, J.A., Dupuis, J., Hypponen, E., Spector, T.D. 2010. Common genetic determinants of vitamin D insufficiency: the sunlight consortium. Lancet. 376(9736):180-188. Interpretive Summary: Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D deficiency has been linked to a number of other disorders , including diabetes, cancer, and cardiovascular disease. In humans, vitamin D concentrations are determined by sun exposure and dietary intake, but there is also evidence suggesting that genetic factors may also play a role. We performed a genome-wide association study of vitamin D concentrations among ~30,000 individuals of European descent from 15 different studies. Five studies were designated as discovery studies (studying 16,125 individuals), in which the genetic factors influencing vitamin D concentrations were identified. There were 10 additional studies (studying 17,744 individuals) used to replicate the findings from the discovery studies. Vitamin D insufficiency was defined as vitamin D concentrations below 75 nmol/L. Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1 and CYP24A1), and vitamin D transport (GC) were found to influence vitamin D concentrations. These variants were significant in the discovery cohorts and confirmed in the replication cohorts. A genotype score was constructed using these three confirmed variants. Those with the highest genotype scores had a 2.5-fold greater likelihood of vitamin D insufficiency. In conclusion, genetic variation identifies individuals of European descent who have substantially elevated risk of vitamin D deficiency. The results are valuable for human nutrition managements. Technical Abstract: Background: Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role. Methods: We performed a genome-wide association study of 25-OH D among ~30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L. Findings: Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 x 10-109 for rs2282679, in GC); 11q12 (P=2.1 x 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 x 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 x 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2.5-fold elevated odds of vitamin D insufficiency (P=2.3 x 10-48). Interpretation: Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1 and CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency. |