Common genetic determinants of vitamin D insufficiency: a genome-wide association study

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

Research output: Contribution to journalArticle

994 Citations (Scopus)

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=1.9x10(-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.

Original languageEnglish
Pages (from-to)180-188
Number of pages9
JournalThe Lancet
Volume376
Issue number9736
DOIs
Publication statusPublished - 17 Jul 2010

Keywords

  • D-binding protein
  • randomized controlled-trials
  • lemli-opitz-syndrome
  • D deficiency
  • serum 25-hydroxyvitamin-D
  • plasma-concentrations
  • D supplementation
  • cancer risk
  • metaanalysis
  • calcium

Cite this

Wang, T. J., Zhang, F., Richards, J. B., Kestenbaum, B., van Meurs, J. B., Berry, D., ... Spector, T. D. (2010). Common genetic determinants of vitamin D insufficiency: a genome-wide association study. The Lancet, 376(9736), 180-188. https://doi.org/10.1016/S0140-6736(10)60588-0

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

In: The Lancet, Vol. 376, No. 9736, 17.07.2010, p. 180-188.

Research output: Contribution to journalArticle

Wang, TJ, Zhang, F, Richards, JB, Kestenbaum, B, van Meurs, JB, Berry, D, Kiel, DP, Streeten, EA, Ohlsson, C, Koller, DL, Peltonen, L, Cooper, JD, O'Reilly, PF, Houston, DK, Glazer, NL, Vandenput, L, Peacock, M, Shi, J, Rivadeneira, F, McCarthy, MI, Anneli, P, de Boer, IH, Mangino, M, Kato, B, Smyth, DJ, Booth, SL, Jacques, PF, Burke, GL, Goodarzi, M, Cheung, C-L, Wolf, M, Rice, K, Goltzman, D, Hidiroglou, N, Ladouceur, M, Wareham, NJ, Hocking, LJ, Hart, D, Arden, NK, Cooper, C, Malik, S, Fraser, WD, Hartikainen, A-L, Zhai, G, Macdonald, HM, Forouhi, NG, Loos, RJF, Reid, DM, Hakim, A, Dennison, E, Liu, Y, Power, C, Stevens, HE, Jaana, L, Vasan, RS, Soranzo, N, Bojunga, J, Psaty, BM, Lorentzon, M, Foroud, T, Harris, TB, Hofman, A, Jonsson, J-O, Cauley, JA, Uitterlinden, AG, Gibson, Q, Jarvelin, M-R, Karasik, D, Siscovick, DS, Econs, MJ, Kritchevsky, SB, Florez, JC, Todd, JA, Dupuis, J, Hyppoenen, E & Spector, TD 2010, 'Common genetic determinants of vitamin D insufficiency: a genome-wide association study', The Lancet, vol. 376, no. 9736, pp. 180-188. https://doi.org/10.1016/S0140-6736(10)60588-0
Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. The Lancet. 2010 Jul 17;376(9736):180-188. https://doi.org/10.1016/S0140-6736(10)60588-0
Wang, Thomas J. ; Zhang, Feng ; Richards, J. Brent ; Kestenbaum, Bryan ; van Meurs, Joyce B. ; Berry, Diane ; Kiel, Douglas P. ; Streeten, Elizabeth A. ; Ohlsson, Claes ; Koller, Daniel L. ; Peltonen, Leena ; Cooper, Jason D. ; O'Reilly, Paul F. ; Houston, Denise K. ; Glazer, Nicole L. ; Vandenput, Liesbeth ; Peacock, Munro ; Shi, Julia ; Rivadeneira, Fernando ; McCarthy, Mark I. ; Anneli, Pouta ; de Boer, Ian H. ; Mangino, Massimo ; Kato, Bernet ; Smyth, Deborah J. ; Booth, Sarah L. ; Jacques, Paul F. ; Burke, Greg L. ; Goodarzi, Mark ; Cheung, Ching-Lung ; Wolf, Myles ; Rice, Kenneth ; Goltzman, David ; Hidiroglou, Nick ; Ladouceur, Martin ; Wareham, Nicholas J. ; Hocking, Lynne J. ; Hart, Deborah ; Arden, Nigel K. ; Cooper, Cyrus ; Malik, Suneil ; Fraser, William D. ; Hartikainen, Anna-Liisa ; Zhai, Guangju ; Macdonald, Helen M. ; Forouhi, Nita G. ; Loos, Ruth J. F. ; Reid, David M. ; Hakim, Alan ; Dennison, Elaine ; Liu, Yongmei ; Power, Chris ; Stevens, Helen E. ; Jaana, Laitinen ; Vasan, Ramachandran S. ; Soranzo, Nicole ; Bojunga, Joerg ; Psaty, Bruce M. ; Lorentzon, Mattias ; Foroud, Tatiana ; Harris, Tamara B. ; Hofman, Albert ; Jonsson, John-Olov ; Cauley, Jane A. ; Uitterlinden, Andre G. ; Gibson, Quince ; Jarvelin, Marjo-Riitta ; Karasik, David ; Siscovick, David S. ; Econs, Michael J. ; Kritchevsky, Stephen B. ; Florez, Jose C. ; Todd, John A. ; Dupuis, Josee ; Hyppoenen, Elina ; Spector, Timothy D. / Common genetic determinants of vitamin D insufficiency : a genome-wide association study. In: The Lancet. 2010 ; Vol. 376, No. 9736. pp. 180-188.
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title = "Common genetic determinants of vitamin D insufficiency: a genome-wide association study",
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=1.9x10(-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.",
keywords = "D-binding protein, randomized controlled-trials, lemli-opitz-syndrome, D deficiency, serum 25-hydroxyvitamin-D, plasma-concentrations, D supplementation, cancer risk, metaanalysis, calcium",
author = "Wang, {Thomas J.} and Feng Zhang and Richards, {J. Brent} and Bryan Kestenbaum and {van Meurs}, {Joyce B.} and Diane Berry and Kiel, {Douglas P.} and Streeten, {Elizabeth A.} and Claes Ohlsson and Koller, {Daniel L.} and Leena Peltonen and Cooper, {Jason D.} and O'Reilly, {Paul F.} and Houston, {Denise K.} and Glazer, {Nicole L.} and Liesbeth Vandenput and Munro Peacock and Julia Shi and Fernando Rivadeneira and McCarthy, {Mark I.} and Pouta Anneli and {de Boer}, {Ian H.} and Massimo Mangino and Bernet Kato and Smyth, {Deborah J.} and Booth, {Sarah L.} and Jacques, {Paul F.} and Burke, {Greg L.} and Mark Goodarzi and Ching-Lung Cheung and Myles Wolf and Kenneth Rice and David Goltzman and Nick Hidiroglou and Martin Ladouceur and Wareham, {Nicholas J.} and Hocking, {Lynne J.} and Deborah Hart and Arden, {Nigel K.} and Cyrus Cooper and Suneil Malik and Fraser, {William D.} and Anna-Liisa Hartikainen and Guangju Zhai and Macdonald, {Helen M.} and Forouhi, {Nita G.} and Loos, {Ruth J. F.} and Reid, {David M.} and Alan Hakim and Elaine Dennison and Yongmei Liu and Chris Power and Stevens, {Helen E.} and Laitinen Jaana and Vasan, {Ramachandran S.} and Nicole Soranzo and Joerg Bojunga and Psaty, {Bruce M.} and Mattias Lorentzon and Tatiana Foroud and Harris, {Tamara B.} and Albert Hofman and John-Olov Jonsson and Cauley, {Jane A.} and Uitterlinden, {Andre G.} and Quince Gibson and Marjo-Riitta Jarvelin and David Karasik and Siscovick, {David S.} and Econs, {Michael J.} and Kritchevsky, {Stephen B.} and Florez, {Jose C.} and Todd, {John A.} and Josee Dupuis and Elina Hyppoenen and Spector, {Timothy D.}",
year = "2010",
month = "7",
day = "17",
doi = "10.1016/S0140-6736(10)60588-0",
language = "English",
volume = "376",
pages = "180--188",
journal = "The Lancet",
issn = "0140-6736",
publisher = "ACADEMIC PRESS INC ELSEVIER SCIENCE",
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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, Joerg

AU - Psaty, Bruce M.

AU - Lorentzon, Mattias

AU - Foroud, Tatiana

AU - Harris, Tamara B.

AU - Hofman, Albert

AU - Jonsson, John-Olov

AU - Cauley, Jane A.

AU - Uitterlinden, Andre G.

AU - Gibson, Quince

AU - Jarvelin, 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 - Hyppoenen, Elina

AU - Spector, Timothy D.

PY - 2010/7/17

Y1 - 2010/7/17

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=1.9x10(-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.

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=1.9x10(-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.

KW - D-binding protein

KW - randomized controlled-trials

KW - lemli-opitz-syndrome

KW - D deficiency

KW - serum 25-hydroxyvitamin-D

KW - plasma-concentrations

KW - D supplementation

KW - cancer risk

KW - metaanalysis

KW - calcium

U2 - 10.1016/S0140-6736(10)60588-0

DO - 10.1016/S0140-6736(10)60588-0

M3 - Article

VL - 376

SP - 180

EP - 188

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9736

ER -