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United States Department of Agriculture

Agricultural Research Service

Research Project: MUSCULOSKELETAL HEALTH IN THE ELDERLY Title: Common genetic determinants of vitamin D insufficiency: the sunlight consortium

Authors
item Wang, Thomas J -
item Feng, Zhang -
item Richards, Brent -
item Kestenbaum, Bryan -
item Van Meurs, Joyce B -
item Berry, Diane -
item Kiel, Douglas -
item Streeten, Elizabeth A -
item Ohlsson, Claes -
item Koller, Daniel L -
item Jarvelin, Marjo-Riitta -
item Cooper, Jason D -
item O'Reilly, Paul F -
item Houston, Denise K -
item Glazer, Nicole L -
item Vandenput, Liesbeth -
item Peacock, Munro -
item Shi, Julia -
item Rivadeneira, Fernando -
item Mccarthy, Mark I -
item Anneli, Pouta -
item DE Boer, Ian H -
item Mangino, Massimo -
item Kato, Bernet -
item Smyth, Deborah J -
item Booth, Sarah L -
item Jacques, Paul F -
item Burke, Greg L -
item Goodarzi, Mark -
item Cheung, Ching-Lung -
item Wolf, Myles -
item Rice, Kenneth -
item Goltzman, David -
item Hidiroglou, Nick -
item Ladouceur, Martin -
item Hui, Siu L -
item Wareham, Nicholas J -
item Hocking, Lynne J -
item Hart, Deborah -
item Arden, Nigel K -
item Copper, Cyrus -
item Malik, Suneil -
item Fraser, William D -
item Hartikainen, Anna-Lisa -
item Zhai, Guangju -
item Macdonald, Helen -
item Forouhi, Nita G -
item Loos, Ruth J F -
item Reid, David M -
item Hakim, Alan -
item Dennison, Elaine -
item Liu, Yongmei -
item Power, Chris -
item Stevens, Helen E -
item Jaana, Laitinen -
item Vasan, Ramachandran S -
item Soranzo, Nicole -
item Bojunga, Joerg -
item Pstay, Bruce M -
item Lorentzon, Mattias -
item Foroud, Tatiana -
item Harris, Tamara B -
item Hofman, Albert -
item Jansson, John-Olov -
item Cauley, Jane A -
item Uitterlinden, Andre G -
item Gibson, Quince -
item Palotie, Leena -
item Karasik, David S -
item Econs, Michael J -
item Kritchevsky, Stephen B -
item Florez, Jose C -
item Todd, John A -
item Dupuis, Josee -
item Hypponen, Elina -
item Spector, Timothy D -

Submitted to: Lancet
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 20, 2010
Publication Date: July 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.

Last Modified: 12/18/2014