Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Xia Jiang; Paul F. O'Reilly; Hugues Aschard; Yi Hsiang Hsu; J. Brent Richards; Josée Dupuis; Erik Ingelsson; David Karasik; Stefan Pilz; DIane Berry; Bryan Kestenbaum; Jusheng Zheng; Jianan Luan; Eleni Sofianopoulou; Elizabeth A. Streeten; Demetrius Albanes; Pamela L. Lutsey; Lu Yao; Weihong Tang; Michael J. Econs; Henri Wallaschofski; Henry Völzke; Ang Zhou; Chris Power; Mark I. McCarthy; Erin D. Michos; Eric Boerwinkle; Stephanie J. Weinstein; Neal D. Freedman; Wen Yi Huang; Natasja M. Van Schoor; Nathalie Van Der Velde; Lisette C.P.G.M.De Groot; Anke Enneman; L. Adrienne Cupples; Sarah L. Booth; Ramachandran S. Vasan; Ching Ti Liu; Yanhua Zhou; Samuli Ripatti; Claes Ohlsson; Liesbeth Vandenput; Mattias Lorentzon; Johan G. Eriksson; M. Kyla Shea; Denise K. Houston; Stephen B. Kritchevsky; Yongmei Liu; Kurt K. Lohman; Luigi Ferrucci; Munro Peacock; Christian Gieger; Marian Beekman; Eline Slagboom; Joris Deelen; DIana Van Heemst; Marcus E. Kleber; Winfried März; Ian H. De Boer; Alexis C. Wood; Jerome I. Rotter; Stephen S. Rich; Cassianne Robinson-Cohen; Martin Den Heijer; Marjo Riitta Jarvelin; Alana Cavadino; Peter K. Joshi; James F. Wilson; Caroline Hayward; Lars Lind; Karl Michaëlsson; Stella Trompet; M. Carola Zillikens; Andre G. Uitterlinden; Fernando Rivadeneira; Linda Broer; Lina Zgaga; Harry Campbell; Evropi Theodoratou; Susan M. Farrington; Maria Timofeeva; Malcolm G. Dunlop; Ana M. Valdes; Emmi Tikkanen; Terho Lehtimäki; Leo Pekka Lyytikäinen; Mika Kähönen; Olli T. Raitakari; Vera Mikkilä; M. Arfan Ikram; Naveed Sattar; J. Wouter Jukema; Nicholas J. Wareham; Claudia Langenberg; Nita G. Forouhi; Thomas E. Gundersen; Kay Tee Khaw; Adam S. Butterworth; John Danesh; Timothy Spector; Thomas J. Wang; Elina Hyppönen; Peter Kraft; Douglas P. Kiel

doi:10.1038/s41467-017-02662-2

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Xia Jiang, Paul F. O'Reilly, Hugues Aschard, Yi Hsiang Hsu, J. Brent Richards, Josée Dupuis, Erik Ingelsson, David Karasik, Stefan Pilz, DIane Berry, Bryan Kestenbaum, Jusheng Zheng, Jianan Luan, Eleni Sofianopoulou, Elizabeth A. Streeten, Demetrius Albanes, Pamela L. Lutsey, Lu Yao, Weihong Tang, Michael J. EconsHenri Wallaschofski, Henry Völzke, Ang Zhou, Chris Power, Mark I. McCarthy, Erin D. Michos, Eric Boerwinkle, Stephanie J. Weinstein, Neal D. Freedman, Wen Yi Huang, Natasja M. Van Schoor, Nathalie Van Der Velde, Lisette C.P.G.M.De Groot, Anke Enneman, L. Adrienne Cupples, Sarah L. Booth, Ramachandran S. Vasan, Ching Ti Liu, Yanhua Zhou, Samuli Ripatti, Claes Ohlsson, Liesbeth Vandenput, Mattias Lorentzon, Johan G. Eriksson, M. Kyla Shea, Denise K. Houston, Stephen B. Kritchevsky, Yongmei Liu, Kurt K. Lohman, Luigi Ferrucci, Munro Peacock, Christian Gieger, Marian Beekman, Eline Slagboom, Joris Deelen, DIana Van Heemst, Marcus E. Kleber, Winfried März, Ian H. De Boer, Alexis C. Wood, Jerome I. Rotter, Stephen S. Rich, Cassianne Robinson-Cohen, Martin Den Heijer, Marjo Riitta Jarvelin, Alana Cavadino, Peter K. Joshi, James F. Wilson, Caroline Hayward, Lars Lind, Karl Michaëlsson, Stella Trompet, M. Carola Zillikens, Andre G. Uitterlinden, Fernando Rivadeneira, Linda Broer, Lina Zgaga, Harry Campbell, Evropi Theodoratou, Susan M. Farrington, Maria Timofeeva, Malcolm G. Dunlop, Ana M. Valdes, Emmi Tikkanen, Terho Lehtimäki, Leo Pekka Lyytikäinen, Mika Kähönen, Olli T. Raitakari, Vera Mikkilä, M. Arfan Ikram, Naveed Sattar, J. Wouter Jukema, Nicholas J. Wareham, Claudia Langenberg, Nita G. Forouhi, Thomas E. Gundersen, Kay Tee Khaw, Adam S. Butterworth, John Danesh, Timothy Spector, Thomas J. Wang, Elina Hyppönen, Peter Kraft, Douglas P. Kiel

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Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10^-9 at rs8018720 in SEC23A, and P = 1.9×10^-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Original language	English (US)
Article number	260
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02662-2
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-017-02662-2

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Jiang, X., O'Reilly, P. F., Aschard, H., Hsu, Y. H., Richards, J. B., Dupuis, J., Ingelsson, E., Karasik, D., Pilz, S., Berry, DI., Kestenbaum, B., Zheng, J., Luan, J., Sofianopoulou, E., Streeten, E. A., Albanes, D., Lutsey, P. L., Yao, L., Tang, W., ... Kiel, D. P. (2018). Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nature communications, 9(1), Article 260. https://doi.org/10.1038/s41467-017-02662-2

Jiang, X, O'Reilly, PF, Aschard, H, Hsu, YH, Richards, JB, Dupuis, J, Ingelsson, E, Karasik, D, Pilz, S, Berry, DI, Kestenbaum, B, Zheng, J, Luan, J, Sofianopoulou, E, Streeten, EA, Albanes, D, Lutsey, PL, Yao, L, Tang, W, Econs, MJ, Wallaschofski, H, Völzke, H, Zhou, A, Power, C, McCarthy, MI, Michos, ED, Boerwinkle, E, Weinstein, SJ, Freedman, ND, Huang, WY, Van Schoor, NM, Van Der Velde, N, Groot, LCPGMD, Enneman, A, Cupples, LA, Booth, SL, Vasan, RS, Liu, CT, Zhou, Y, Ripatti, S, Ohlsson, C, Vandenput, L, Lorentzon, M, Eriksson, JG, Shea, MK, Houston, DK, Kritchevsky, SB, Liu, Y, Lohman, KK, Ferrucci, L, Peacock, M, Gieger, C, Beekman, M, Slagboom, E, Deelen, J, Heemst, DIV, Kleber, ME, März, W, De Boer, IH, Wood, AC, Rotter, JI, Rich, SS, Robinson-Cohen, C, Den Heijer, M, Jarvelin, MR, Cavadino, A, Joshi, PK, Wilson, JF, Hayward, C, Lind, L, Michaëlsson, K, Trompet, S, Zillikens, MC, Uitterlinden, AG, Rivadeneira, F, Broer, L, Zgaga, L, Campbell, H, Theodoratou, E, Farrington, SM, Timofeeva, M, Dunlop, MG, Valdes, AM, Tikkanen, E, Lehtimäki, T, Lyytikäinen, LP, Kähönen, M, Raitakari, OT, Mikkilä, V, Ikram, MA, Sattar, N, Jukema, JW, Wareham, NJ, Langenberg, C, Forouhi, NG, Gundersen, TE, Khaw, KT, Butterworth, AS, Danesh, J, Spector, T, Wang, TJ, Hyppönen, E, Kraft, P & Kiel, DP 2018, 'Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels', Nature communications, vol. 9, no. 1, 260. https://doi.org/10.1038/s41467-017-02662-2

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title = "Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels",

abstract = "Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.",

author = "Xia Jiang and O'Reilly, {Paul F.} and Hugues Aschard and Hsu, {Yi Hsiang} and Richards, {J. Brent} and Jos{\'e}e Dupuis and Erik Ingelsson and David Karasik and Stefan Pilz and DIane Berry and Bryan Kestenbaum and Jusheng Zheng and Jianan Luan and Eleni Sofianopoulou and Streeten, {Elizabeth A.} and Demetrius Albanes and Lutsey, {Pamela L.} and Lu Yao and Weihong Tang and Econs, {Michael J.} and Henri Wallaschofski and Henry V{\"o}lzke and Ang Zhou and Chris Power and McCarthy, {Mark I.} and Michos, {Erin D.} and Eric Boerwinkle and Weinstein, {Stephanie J.} and Freedman, {Neal D.} and Huang, {Wen Yi} and {Van Schoor}, {Natasja M.} and {Van Der Velde}, Nathalie and Groot, {Lisette C.P.G.M.De} and Anke Enneman and Cupples, {L. Adrienne} and Booth, {Sarah L.} and Vasan, {Ramachandran S.} and Liu, {Ching Ti} and Yanhua Zhou and Samuli Ripatti and Claes Ohlsson and Liesbeth Vandenput and Mattias Lorentzon and Eriksson, {Johan G.} and Shea, {M. Kyla} and Houston, {Denise K.} and Kritchevsky, {Stephen B.} and Yongmei Liu and Lohman, {Kurt K.} and Luigi Ferrucci and Munro Peacock and Christian Gieger and Marian Beekman and Eline Slagboom and Joris Deelen and Heemst, {DIana Van} and Kleber, {Marcus E.} and Winfried M{\"a}rz and {De Boer}, {Ian H.} and Wood, {Alexis C.} and Rotter, {Jerome I.} and Rich, {Stephen S.} and Cassianne Robinson-Cohen and {Den Heijer}, Martin and Jarvelin, {Marjo Riitta} and Alana Cavadino and Joshi, {Peter K.} and Wilson, {James F.} and Caroline Hayward and Lars Lind and Karl Micha{\"e}lsson and Stella Trompet and Zillikens, {M. Carola} and Uitterlinden, {Andre G.} and Fernando Rivadeneira and Linda Broer and Lina Zgaga and Harry Campbell and Evropi Theodoratou and Farrington, {Susan M.} and Maria Timofeeva and Dunlop, {Malcolm G.} and Valdes, {Ana M.} and Emmi Tikkanen and Terho Lehtim{\"a}ki and Lyytik{\"a}inen, {Leo Pekka} and Mika K{\"a}h{\"o}nen and Raitakari, {Olli T.} and Vera Mikkil{\"a} and Ikram, {M. Arfan} and Naveed Sattar and Jukema, {J. Wouter} and Wareham, {Nicholas J.} and Claudia Langenberg and Forouhi, {Nita G.} and Gundersen, {Thomas E.} and Khaw, {Kay Tee} and Butterworth, {Adam S.} and John Danesh and Timothy Spector and Wang, {Thomas J.} and Elina Hypp{\"o}nen and Peter Kraft and Kiel, {Douglas P.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-017-02662-2",

language = "English (US)",

volume = "9",

journal = "Nature communications",

issn = "2041-1723",

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TY - JOUR

T1 - Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

AU - Jiang, Xia

AU - O'Reilly, Paul F.

AU - Aschard, Hugues

AU - Hsu, Yi Hsiang

AU - Richards, J. Brent

AU - Dupuis, Josée

AU - Ingelsson, Erik

AU - Karasik, David

AU - Pilz, Stefan

AU - Berry, DIane

AU - Kestenbaum, Bryan

AU - Zheng, Jusheng

AU - Luan, Jianan

AU - Sofianopoulou, Eleni

AU - Streeten, Elizabeth A.

AU - Albanes, Demetrius

AU - Lutsey, Pamela L.

AU - Yao, Lu

AU - Tang, Weihong

AU - Econs, Michael J.

AU - Wallaschofski, Henri

AU - Völzke, Henry

AU - Zhou, Ang

AU - Power, Chris

AU - McCarthy, Mark I.

AU - Michos, Erin D.

AU - Boerwinkle, Eric

AU - Weinstein, Stephanie J.

AU - Freedman, Neal D.

AU - Huang, Wen Yi

AU - Van Schoor, Natasja M.

AU - Van Der Velde, Nathalie

AU - Groot, Lisette C.P.G.M.De

AU - Enneman, Anke

AU - Cupples, L. Adrienne

AU - Booth, Sarah L.

AU - Vasan, Ramachandran S.

AU - Liu, Ching Ti

AU - Zhou, Yanhua

AU - Ripatti, Samuli

AU - Ohlsson, Claes

AU - Vandenput, Liesbeth

AU - Lorentzon, Mattias

AU - Eriksson, Johan G.

AU - Shea, M. Kyla

AU - Houston, Denise K.

AU - Kritchevsky, Stephen B.

AU - Liu, Yongmei

AU - Lohman, Kurt K.

AU - Ferrucci, Luigi

AU - Peacock, Munro

AU - Gieger, Christian

AU - Beekman, Marian

AU - Slagboom, Eline

AU - Deelen, Joris

AU - Heemst, DIana Van

AU - Kleber, Marcus E.

AU - März, Winfried

AU - De Boer, Ian H.

AU - Wood, Alexis C.

AU - Rotter, Jerome I.

AU - Rich, Stephen S.

AU - Robinson-Cohen, Cassianne

AU - Den Heijer, Martin

AU - Jarvelin, Marjo Riitta

AU - Cavadino, Alana

AU - Joshi, Peter K.

AU - Wilson, James F.

AU - Hayward, Caroline

AU - Lind, Lars

AU - Michaëlsson, Karl

AU - Trompet, Stella

AU - Zillikens, M. Carola

AU - Uitterlinden, Andre G.

AU - Rivadeneira, Fernando

AU - Broer, Linda

AU - Zgaga, Lina

AU - Campbell, Harry

AU - Theodoratou, Evropi

AU - Farrington, Susan M.

AU - Timofeeva, Maria

AU - Dunlop, Malcolm G.

AU - Valdes, Ana M.

AU - Tikkanen, Emmi

AU - Lehtimäki, Terho

AU - Lyytikäinen, Leo Pekka

AU - Kähönen, Mika

AU - Raitakari, Olli T.

AU - Mikkilä, Vera

AU - Ikram, M. Arfan

AU - Sattar, Naveed

AU - Jukema, J. Wouter

AU - Wareham, Nicholas J.

AU - Langenberg, Claudia

AU - Forouhi, Nita G.

AU - Gundersen, Thomas E.

AU - Khaw, Kay Tee

AU - Butterworth, Adam S.

AU - Danesh, John

AU - Spector, Timothy

AU - Wang, Thomas J.

AU - Hyppönen, Elina

AU - Kraft, Peter

AU - Kiel, Douglas P.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

AB - Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

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U2 - 10.1038/s41467-017-02662-2

DO - 10.1038/s41467-017-02662-2

M3 - Article

C2 - 29343764

AN - SCOPUS:85041401774

SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 260

ER -

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

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