Journal
LANCET
Volume 376, Issue 9736, Pages 180-188Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0140-6736(10)60588-0
Keywords
-
Categories
Funding
- Novartis
- Roche
- Amgen
- NIH/NHLBI [N01-HC-25195]
- American Heart Association
- US Department of Agriculture, Agricultural Research Service [58-1950-7-707]
- National Institute of Aging [AG14759]
- National Institute of Arthritis, Musculoskeletal, and Skin Diseases
- National Institute on Aging [R01 AR/AG 41398]
- Affymetrix Inc [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
- Wellcome Trust
- Arthritis Research Campaign
- European Community [FP7/2007-2013, HEALTH-F2-2008-201865-GEFOS, 200800, OA /(FP7/2007-2013), HEALTH-F4-2007-201413, QLG2-CT-2002-01254]
- UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre
- Biotechnology and Biological Sciences Research Council [G20234]
- National Eye Institute (NEI) via an NIH/Center for Inherited Disease Research (CIDR)
- Netherlands Organization of Scientific Research (NWO) [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93-015: RIDE2]
- Netherlands Genomics Initiative/NWO [050-060-810]
- European Commission [HEALTH-F2-2008-201865-GEFOS, HEALTH-F2-2008-00-TREAT-OA]
- Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development
- Research Institute for Diseases in the Elderly
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission
- Municipality of Rotterdam
- MRC [MC_U106188470, G0400546, G0000934, G0701863, G0600705, G0601653, MC_UP_A100_1003] Funding Source: UKRI
- Medical Research Council [MC_U106188470, MC_UP_A100_1003, MC_U106179471, G0801462, G0400546, G0000934, G0701863, G0400546B, MC_UP_A620_1014, G0601653, U1475000001, G0600705] Funding Source: researchfish
- National Institute for Health Research [PHCS/C4/4/016, NF-SI-0508-10275, NF-SI-0508-10082] Funding Source: researchfish
Ask authors/readers for more resources
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(-22) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available