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=1·9×10-109 for rs2282679, in GC); 11q12 (p=2·1×10-27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10-10 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= 2·3×10-48) or lower than 50 nmol/L (1·92, 1·70-2·16, p=1·0×10-26) 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). ].
| Original language | English |
|---|---|
| Pages (from-to) | 180-188 |
| Number of pages | 9 |
| Journal | The Lancet |
| Volume | 376 |
| Issue number | 9736 |
| DOIs | |
| Publication status | Published or Issued - 2010 |
ASJC Scopus subject areas
- General Medicine
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In: The Lancet, Vol. 376, No. 9736, 2010, p. 180-188.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Common genetic determinants of vitamin D insufficiency
T2 - A genome-wide association study
AU - Wang, Thomas J.
AU - Zhang, Feng
AU - Richards, J. Brent
AU - Kestenbaum, Bryan
AU - Van Meurs, Joyce B.
AU - Berry, Diane
AU - Kiel, Douglas P.
AU - Streeten, Elizabeth A.
AU - Ohlsson, Claes
AU - Koller, Daniel L.
AU - Peltonen, Leena
AU - Cooper, Jason D.
AU - O'Reilly, Paul F.
AU - Houston, Denise K.
AU - Glazer, Nicole L.
AU - Vandenput, Liesbeth
AU - Peacock, Munro
AU - Shi, Julia
AU - Rivadeneira, Fernando
AU - McCarthy, Mark I.
AU - Anneli, Pouta
AU - De Boer, Ian H.
AU - Mangino, Massimo
AU - Kato, Bernet
AU - Smyth, Deborah J.
AU - Booth, Sarah L.
AU - Jacques, Paul F.
AU - Burke, Greg L.
AU - Goodarzi, Mark
AU - Cheung, Ching Lung
AU - Wolf, Myles
AU - Rice, Kenneth
AU - Goltzman, David
AU - Hidiroglou, Nick
AU - Ladouceur, Martin
AU - Wareham, Nicholas J.
AU - Hocking, Lynne J.
AU - Hart, Deborah
AU - Arden, Nigel K.
AU - Cooper, Cyrus
AU - Malik, Suneil
AU - Fraser, William D.
AU - Hartikainen, Anna Liisa
AU - Zhai, Guangju
AU - Macdonald, Helen M.
AU - Forouhi, Nita G.
AU - Loos, Ruth J F
AU - Reid, David M.
AU - Hakim, Alan
AU - Dennison, Elaine
AU - Liu, Yongmei
AU - Power, Chris
AU - Stevens, Helen E.
AU - Jaana, Laitinen
AU - Vasan, Ramachandran S.
AU - Soranzo, Nicole
AU - Bojunga, Jörg
AU - Psaty, Bruce M.
AU - Lorentzon, Mattias
AU - Foroud, Tatiana
AU - Harris, Tamara B.
AU - Hofman, Albert
AU - Jansson, John Olov
AU - Cauley, Jane A.
AU - Uitterlinden, Andre G.
AU - Gibson, Quince
AU - Järvelin, Marjo Riitta
AU - Karasik, David
AU - Siscovick, David S.
AU - Econs, Michael J.
AU - Kritchevsky, Stephen B.
AU - Florez, Jose C.
AU - Todd, John A.
AU - Dupuis, Josee
AU - Hyppönen, Elina
AU - Spector, Timothy D.
N1 - Funding Information: Health, Aging and Body Composition Study This research was supported by the Intramural Research Program of the NIH National Institute on Aging and National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103 , and N01-AG-6-2106 . Assessment of 25-hydroxyvitamin D concentrations was funded by a National Institute on Aging grant, R01-AG029364 . The genome-wide association study was funded by a National Institute on Aging grant, R01-AG032098 , and genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from NIH to The Johns Hopkins University (contract number HHSN268200782096C ). Funding Information: The Rotterdam Study This study was funded by the Netherlands Organization of Scientific Research (NWO) Investments ( 175.010.2005.011, 911-03-012 ), the Research Institute for Diseases in the Elderly ( 014-93-015; RIDE2 ), the Netherlands Genomics Initiative/NWO project 050-060-810 , and the European Commission ( HEALTH-F2-2008-201865-GEFOS , and HEALTH-F2-2008-00-TREAT-OA ). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We thank the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. Funding Information: Study of Indiana Women This work was supported by NIH grants P01 AG-18397 and M01 RR-00750 . Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from NIH to The Johns Hopkins University, contract number HHSN268200782096C . This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine . Funding Information: 1958 British Birth Cohort The project was funded by the UK Medical Research Council (MRC) (project grant G0601653 ), and 25-hydroxyvitamin D assays by the BUPA foundation. EH is funded by a UK Department of Health Public Health Career Scientist Award. Use of DNA from this cohort was funded by MRC grant G0000934 and Wellcome Trust grant 068545/Z/02 . This research used resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418 . This study makes use of data generated by the Wellcome Trust Case-Control Consortium . A full list of investigators who contributed to generation of the data is available from the Wellcome Trust Case-Control Consortium website. Funding for the project was provided by the Wellcome Trust under award 076113 . The MRC Centre of Epidemiology for Child Health is funded by the MRC. Great Ormond Street Hospital/University College London, Institute of Child Health receives a proportion of funding from the Department of Health's NIHR ('Biomedical Research Centres' funding). Funding Information: Gothenberg Osteoporosis and Obesity Determinants (GOOD) Study Financial support was received from the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg's Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Sahlgrenska Center for Cardiovascular and Metabolic Research (CMR, no A305:188), which is supported by the Swedish Strategic Foundation. Funding Information: Cardiovascular Health Study Research for this cohort that was reported in this article was supported by contract numbers N01-HC-85079 to N01-HC-85086, N01-HC-35129, N01 HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133 , grant numbers U01 HL080295, R01 HL084443, R01 HL087652 , and R01 AG027002 from NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal investigators and institutions is available at the Cardiovascular Health Study website . DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00069 to the Cedars-Sinai General Clinical Research Center Genotyping core and NIDDK grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: Aberdeen Prospective Osteoporosis Screening Study Funding for cohort sample collection and analysis was supported in part by grants from the European Commission ( QLRT-2001-02629 ) and the UK Food Standards Agency. We thank the clinical research staff in the Bone and Musculoskeletal Research Programme for all their hard work, and all the women who participated in the study. Funding Information: North Finland Birth Cohort 1966 The project was funded by the MRC (project grant G0601653 ). Financial support was received from the Academy of Finland (project grants 104781, 120315, 1114194 and Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, Finland, NHLBI grant 5R01HL087679-02 through the STAMPEED program ( 1RL1MH083268-01 ), ENGAGE project and grant agreement HEALTH-F4-2007-201413 , MRC ( studentship grant G0500539 , centre grant G0600705 ), the Wellcome Trust (project grant GR069224 ), UK. DNA extractions, sample quality controls, biobank up-keeping, and aliquotting were done at the National Public Health Institute, Biomedicum Helsinki, Finland and supported financially by the Academy of Finland and Biocentrum Helsinki. Funding Information: The Amish Family Osteoporosis Study The Amish Family Osteoporosis Study was funded by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases ( R01 AR46838 ). Funding Information: Framingham Heart Study The Framingham Heart Study of the National Heart, Lung and Blood Institute (NHLBI) of the US National Institutes of Health (NIH) and Boston University School of Medicine is supported by the NIH/NHLBI contract N01-HC-25195 . The present study received support from the American Heart Association, the US Department of Agriculture, Agricultural Research Service (under Cooperative Agreement No 58-1950-7-707 ), and the National Institute of Aging ( AG14759 ). DK was supported by a grant from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases and the National Institute on Aging ( R01 AR/AG 41398 ). The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. This work was partly supported by a contract with Affymetrix Inc for genotyping services (Contract No N02-HL-6-4278 ). A portion of this research used the Linux Cluster for Genetic Analysis, which is funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Funding Information: TwinsUK and Chingford The study was funded by the Wellcome Trust, Arthritis Research Campaign, European Community's Seventh Framework Programme ( FP7/2007-2013 )/grant agreement HEALTH-F2-2008-201865-GEFOS and Seventh Framework Programme grant 200800 Treat OA/(FP7/2007-2013 ), ENGAGE project grant agreement HEALTH-F4-2007-201413 , and the FP-5 GenomEUtwin Project ( QLG2-CT-2002-01254 ). The study also receives support from the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. TDS is an NIHR senior investigator. The project also received support from a Biotechnology and Biological Sciences Research Council project grant. ( G20234 ). The authors acknowledge the funding and support of the National Eye Institute (NEI) via an NIH/Center for Inherited Disease Research (CIDR) genotyping project. We thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, quality control, and genotyping; Le Centre National de Génotypage, France, for genotyping; Duke University, NC, USA, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki. Genotyping was also done by CIDR as part of an NEI/NIH project grant. Funding Information: Canadian Multicentre Osteoporosis Study CaMoS is funded by the Canadian Institutes of Health Research (CIHR). JBR is a clinical investigator of the CIHR and an Osteoporosis Canada New Investigator. This work was supported by grants to JBR from the CIHR and Canadian Foundation for Innovation. We acknowledge the support and funding of the Public Health Agency of Canada to assay vitamin D levels, the expert technical support of Kurtis Sarafin and Jenn Kreiger of Health Canada (vitamin D measurements) and the input of Linda S Greene-Finestone and Ross Duncan. Funding Information: Other The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award ( 079895 ). This work was also supported by JDRF, the Wellcome Trust, and the NIHR Cambridge Biomedical Centre. Funding Information: Hertfordshire This study was funded by the UK MRC and the Arthritis Research Campaign.
PY - 2010
Y1 - 2010
N2 - 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=1·9×10-109 for rs2282679, in GC); 11q12 (p=2·1×10-27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10-10 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= 2·3×10-48) or lower than 50 nmol/L (1·92, 1·70-2·16, p=1·0×10-26) 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). ].
AB - 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=1·9×10-109 for rs2282679, in GC); 11q12 (p=2·1×10-27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10-10 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= 2·3×10-48) or lower than 50 nmol/L (1·92, 1·70-2·16, p=1·0×10-26) 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). ].
UR - http://www.scopus.com/inward/record.url?scp=77955052903&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(10)60588-0
DO - 10.1016/S0140-6736(10)60588-0
M3 - Article
C2 - 20541252
AN - SCOPUS:77955052903
SN - 0140-6736
VL - 376
SP - 180
EP - 188
JO - The Lancet
JF - The Lancet
IS - 9736
ER -