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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #275372
Title: Common genetic determinants of vitamin D insufficiency: the sunlight consortium

Author
item WANG, THOMAS J - Massachusetts General Hospital
item FENG, ZHANG - King'S College
item RICHARDS, BRENT - McGill University - Canada
item KESTENBAUM, BRYAN - University Of Washington Medical School
item VAN MEURS, JOYCE B - Erasmus Medical Center
item BERRY, DIANE - University College Medical School - London
item KIEL, DOUGLAS - Harvard Medical School
item STREETEN, ELIZABETH A - University Of Maryland
item OHLSSON, CLAES - University Of Goteborg
item KOLLER, DANIEL L - Indiana University School Of Medicine
item JARVELIN, MARJO-RIITTA - Imperial College Of Medicine
item COOPER, JASON D - University Of Cambridge
item O'REILLY, PAUL F - Imperial College Of Medicine
item HOUSTON, DENISE K - Wake Forest School Of Medicine
item GLAZER, NICOLE L - University Of Washington Medical School
item VANDENPUT, LIESBETH - University Of Goteborg
item PEACOCK, MUNRO - Indiana University School Of Medicine
item SHI, JULIA - University Of Maryland
item RIVADENEIRA, FERNANDO - Erasmus Medical Center
item MCCARTHY, MARK I - Oxford University
item ANNELI, POUTA - University Of Oulu
item DE BOER, IAN H - University Of Washington Medical School
item MANGINO, MASSIMO - King'S College
item KATO, BERNET - King'S College
item SMYTH, DEBORAH J - University Of Cambridge
item BOOTH, SARAH L - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item JACQUES, PAUL F - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item BURKE, GREG L - Wake Forest University
item GOODARZI, MARK - Cedars-Sinai Medical Center
item CHEUNG, CHING-LUNG - Hebrew Seniorlife Research
item WOLF, MYLES - University Of Miami
item RICE, KENNETH - University Of Washington Medical School
item GOLTZMAN, DAVID - McGill University - Canada
item HIDIROGLOU, NICK - Health Canada
item LADOUCEUR, MARTIN - McGill University - Canada
item HUI, SIU L - Indiana University School Of Medicine
item WAREHAM, NICHOLAS J - Mrc Human Nutrition Research
item HOCKING, LYNNE J - University Of Aberdeen
item HART, DEBORAH - King'S College
item ARDEN, NIGEL K - University Of Southampton
item COPPER, CYRUS - University Of Southampton
item MALIK, SUNEIL - Public Health Agency Of Canada
item FRASER, WILLIAM D - University Of Liverpool
item HARTIKAINEN, ANNA-LISA - University Of Oulu
item ZHAI, GUANGJU - Luiz De Queiroz College Of Agriculture (ESALQ)
item MACDONALD, HELEN - University Of Aberdeen
item FOROUHI, NITA G - Mrc Human Nutrition Research
item LOOS, RUTH J F - Mrc Human Nutrition Research
item REID, DAVID M - University Of Aberdeen
item HAKIM, ALAN - Whipps Cross University Hosptial
item DENNISON, ELAINE - University Of Southampton
item LIU, YONGMEI - Wake Forest School Of Medicine
item POWER, CHRIS - University College Medical School - London
item STEVENS, HELEN E - University Of Cambridge
item JAANA, LAITINEN - University Of Oulu
item VASAN, RAMACHANDRAN S - Framingham Heart Study
item SORANZO, NICOLE - King'S College
item BOJUNGA, JOERG - Frankfurt University
item PSTAY, BRUCE M - University Of Washington Medical School
item LORENTZON, MATTIAS - University Of Goteborg
item FOROUD, TATIANA - Indiana University School Of Medicine
item HARRIS, TAMARA B - National Institutes Of Health (NIH)
item HOFMAN, ALBERT - Netherlands Genomics Initiative
item JANSSON, JOHN-OLOV - University Of Goteborg
item CAULEY, JANE A - University Of Pittsburgh
item UITTERLINDEN, ANDRE G - Netherlands Genomics Initiative
item GIBSON, QUINCE - Erasmus Medical Center
item PALOTIE, LEENA - Wellcome Trust Sanger Institute
item KARASIK, DAVID S - Harvard Medical School
item ECONS, MICHAEL J - Indiana University School Of Medicine
item KRITCHEVSKY, STEPHEN B - Wake Forest School Of Medicine
item FLOREZ, JOSE C - Harvard Medical School
item TODD, JOHN A - University Of Cambridge
item DUPUIS, JOSEE - Framingham Heart Study
item HYPPONEN, ELINA - University College Medical School - London
item SPECTOR, TIMOTHY D - King'S College

Submitted to: Lancet
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/20/2010
Publication Date: 7/20/2010
Citation: Wang, T., Feng, Z., Richards, B., Kestenbaum, B., Van Meurs, J., Berry, D., Kiel, D., Streeten, E., Ohlsson, C., Koller, D., Jarvelin, M., Cooper, J., O'Reilly, P., Houston, D., Glazer, N., Vandenput, L., Peacock, M., Shi, J., Rivadeneira, F., Mccarthky, M., Anneli, P., De Boer, I., Mangino, M., Kato, B., Smyth, D., Booth, S., Jacques, P., Burke, G., Goodarzi, M., Cheung, C., Wolf, M., Rice, K., Goltzman, D., Hidiroglou, N., Ladouceur, M., Hui, S., Wareham, N., Hocking, L., Hart, D., Arden, N., Copper, C., Malik, S., Fraser, W., Hartikainen, A., Zhai, G., Macdonald, H., Forouhinita G, Loos, R., Reid, D., Hakim, A., Dennison, E., Liu, Y., Power, C., Stevens, H., Jaana, L., Vasan, R., Soranzo, N., Bojunga, J., Pstay, B., Lorentzon, M., Foroud, T., Harris, T., Hofman, A., Jansson, J., Cauley, J., Uitterlinden, A., Gibson, Q., Palotie, L., Karasik, D., Econs, M., Kritchevskyk, S., Florez, J., Todd, J., Dupuis, J., Hypponen, E., Spector, T. 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.