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

TJ Wang; F Zhang; JB Richards; B Kestenbaum; Joyce van Meurs; D Berry; DP Kiel; EA Streeten; C Ohlsson; DL Koller; L Peltonen; JD Cooper; PF O'Reilly; DK Houston; NL Glazer; L Vandenput; M Peacock; J Shi; Fernando Rivadeneira; MI McCarthy; P Anneli; IH (Ian) Boer; M Mangino; B Kato; DJ Smyth; SL Booth; PF Jacques; GL Burke; M Goodarzi; C Cheung; Monique Wolf; K Rice; D Goltzman; N Hidiroglou; M Ladouceur; NJ Wareham; LJ Hocking; Daphne Hart; NK Arden; C Cooper; S Malik; WD Fraser; AL Hartikainen; GJ Zhai; HM Macdonald; NG Forouhi; RJF Loos; DM Reid; A Hakim; E Dennison; YM Liu; C Power; HE Stevens; L Jaana; RS Vasan; N Soranzo; J Bojunga; BM Psaty; M Lorentzon; T Foroud; TB Harris; Bert Hofman; JO Jonsson; JA Cauley; André Uitterlinden; Q Gibson; MR Jarvelin; D Karasik; DS Siscovick; MJ Econs; SB Kritchevsky; JC Florez; JA Todd; J Dupuis; E Hypponen; TD Spector

doi:10.1016/S0140-6736(10)60588-0

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

TJ Wang, F Zhang, JB Richards, B Kestenbaum, Joyce van Meurs, D Berry, DP Kiel, EA Streeten, C Ohlsson, DL Koller, L Peltonen, JD Cooper, PF O'Reilly, DK Houston, NL Glazer, L Vandenput, M Peacock, J Shi, Fernando Rivadeneira, MI McCarthyP Anneli, IH (Ian) Boer, M Mangino, B Kato, DJ Smyth, SL Booth, PF Jacques, GL Burke, M Goodarzi, C Cheung, Monique Wolf, K Rice, D Goltzman, N Hidiroglou, M Ladouceur, NJ Wareham, LJ Hocking, Daphne Hart, NK Arden, C Cooper, S Malik, WD Fraser, AL Hartikainen, GJ Zhai, HM Macdonald, NG Forouhi, RJF Loos, DM Reid, A Hakim, E Dennison, YM Liu, C Power, HE Stevens, L Jaana, RS Vasan, N Soranzo, J Bojunga, BM Psaty, M Lorentzon, T Foroud, TB Harris, Bert Hofman, JO Jonsson, JA Cauley, André Uitterlinden, Q Gibson, MR Jarvelin, D Karasik, DS Siscovick, MJ Econs, SB Kritchevsky, JC Florez, JA Todd, J Dupuis, E Hypponen, TD Spector

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	Undefined/Unknown
Pages (from-to)	180-188
Number of pages	9
Journal	Lancet (UK)
Volume	376
Issue number	9736
DOIs	https://doi.org/10.1016/S0140-6736(10)60588-0
Publication status	Published - 2010

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10.1016/S0140-6736(10)60588-0

http://hdl.handle.net/1765/27771

1384 Citations
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Common genetic determinants of vitamin D insufficiency: A genome-wide association study
the SUNLIGHT Consortium, Feb 2011, In: Obstetrical and Gynecological Survey. 66, 2, p. 91-93 3 p.
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Wang, TJ., Zhang, F., Richards, JB., Kestenbaum, B., van Meurs, J., 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., ... Spector, TD. (2010). Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet (UK), 376(9736), 180-188. https://doi.org/10.1016/S0140-6736(10)60588-0

@article{d990dd7963a740fba7b071355c1852a3,

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.",

author = "TJ Wang and F Zhang and JB Richards and B Kestenbaum and {van Meurs}, Joyce and D Berry and DP Kiel and EA Streeten and C Ohlsson and DL Koller and L Peltonen and JD Cooper and PF O'Reilly and DK Houston and NL Glazer and L Vandenput and M Peacock and J Shi and Fernando Rivadeneira and MI McCarthy and P Anneli and Boer, {IH (Ian)} and M Mangino and B Kato and DJ Smyth and SL Booth and PF Jacques and GL Burke and M Goodarzi and C Cheung and Monique Wolf and K Rice and D Goltzman and N Hidiroglou and M Ladouceur and NJ Wareham and LJ Hocking and Daphne Hart and NK Arden and C Cooper and S Malik and WD Fraser and AL Hartikainen and GJ Zhai and HM Macdonald and NG Forouhi and RJF Loos and DM Reid and A Hakim and E Dennison and YM Liu and C Power and HE Stevens and L Jaana and RS Vasan and N Soranzo and J Bojunga and BM Psaty and M Lorentzon and T Foroud and TB Harris and Bert Hofman and JO Jonsson and JA Cauley and Andr{\'e} Uitterlinden and Q Gibson and MR Jarvelin and D Karasik and DS Siscovick and MJ Econs and SB Kritchevsky and JC Florez and JA Todd and J Dupuis and E Hypponen and TD Spector",

year = "2010",

doi = "10.1016/S0140-6736(10)60588-0",

language = "Undefined/Unknown",

volume = "376",

pages = "180--188",

journal = "Lancet (UK)",

issn = "0140-6736",

publisher = "Elsevier",

number = "9736",

}

Wang, TJ, Zhang, F, Richards, JB, Kestenbaum, B, van Meurs, J, 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, Boer, IH, Mangino, M, Kato, B, Smyth, DJ, Booth, SL, Jacques, PF, Burke, GL, Goodarzi, M, Cheung, C, 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, AL, Zhai, GJ, Macdonald, HM, Forouhi, NG, Loos, RJF, Reid, DM, Hakim, A, Dennison, E, Liu, YM, Power, C, Stevens, HE, Jaana, L, Vasan, RS, Soranzo, N, Bojunga, J, Psaty, BM, Lorentzon, M, Foroud, T, Harris, TB, Hofman, B, Jonsson, JO, Cauley, JA, Uitterlinden, A, Gibson, Q, Jarvelin, MR, Karasik, D, Siscovick, DS, Econs, MJ, Kritchevsky, SB, Florez, JC, Todd, JA, Dupuis, J, Hypponen, E & Spector, TD 2010, 'Common genetic determinants of vitamin D insufficiency: a genome-wide association study', Lancet (UK), vol. 376, no. 9736, pp. 180-188. https://doi.org/10.1016/S0140-6736(10)60588-0

TY - JOUR

T1 - Common genetic determinants of vitamin D insufficiency: a genome-wide association study

AU - Wang, TJ

AU - Zhang, F

AU - Richards, JB

AU - Kestenbaum, B

AU - van Meurs, Joyce

AU - Berry, D

AU - Kiel, DP

AU - Streeten, EA

AU - Ohlsson, C

AU - Koller, DL

AU - Peltonen, L

AU - Cooper, JD

AU - O'Reilly, PF

AU - Houston, DK

AU - Glazer, NL

AU - Vandenput, L

AU - Peacock, M

AU - Shi, J

AU - Rivadeneira, Fernando

AU - McCarthy, MI

AU - Anneli, P

AU - Boer, IH (Ian)

AU - Mangino, M

AU - Kato, B

AU - Smyth, DJ

AU - Booth, SL

AU - Jacques, PF

AU - Burke, GL

AU - Goodarzi, M

AU - Cheung, C

AU - Wolf, Monique

AU - Rice, K

AU - Goltzman, D

AU - Hidiroglou, N

AU - Ladouceur, M

AU - Wareham, NJ

AU - Hocking, LJ

AU - Hart, Daphne

AU - Arden, NK

AU - Cooper, C

AU - Malik, S

AU - Fraser, WD

AU - Hartikainen, AL

AU - Zhai, GJ

AU - Macdonald, HM

AU - Forouhi, NG

AU - Loos, RJF

AU - Reid, DM

AU - Hakim, A

AU - Dennison, E

AU - Liu, YM

AU - Power, C

AU - Stevens, HE

AU - Jaana, L

AU - Vasan, RS

AU - Soranzo, N

AU - Bojunga, J

AU - Psaty, BM

AU - Lorentzon, M

AU - Foroud, T

AU - Harris, TB

AU - Hofman, Bert

AU - Jonsson, JO

AU - Cauley, JA

AU - Uitterlinden, André

AU - Gibson, Q

AU - Jarvelin, MR

AU - Karasik, D

AU - Siscovick, DS

AU - Econs, MJ

AU - Kritchevsky, SB

AU - Florez, JC

AU - Todd, JA

AU - Dupuis, J

AU - Hypponen, E

AU - Spector, TD

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=1.9x10(-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.

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

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

M3 - Article

SN - 0140-6736

VL - 376

SP - 180

EP - 188

JO - Lancet (UK)

JF - Lancet (UK)

IS - 9736

ER -

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

Abstract

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Research output

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

Cite this