Genome-wide Association Study in 79,366 European-ancestry Individuals Informs the Genetic Architecture of 25-Hydroxyvitamin D Levels

Xia Jing; Paul F. O'Reilly; Hugues Aschard; Yi-Hsiang Hsu; J. Brent Richards; Josée Dupuis; Erik Ingelsson; David Karasik; Stefan Pilz; Diane J Berry; Bryan Kestenbaum; Jusheng Zheng; Jian'an Luan; Eleni Sofianopoulou; Elizabeth A Streeten; Demetrius Albanes; Pamela L. Lutsey; Lu Yao; Weihong Tang; Michael J. Econs; Henri Wallaschofski; Henry Volzke; 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 W Enneman; L. Adrienne Cupples; Sarah L. Booth; Ramachandran S. Vasan; Ching-Ti Liu; Yanhua Zhou; Samuli Ripatti; Claes Ohlsson; Liesbeth Vandenput; Mattias Lorentzon; Johan  Eriksson; M Kyla Shea; Denise K Houston; Stephen B. Kritchevsky; Yongmei Liu; Kurt Lohman; Luigi Ferrucci; Munro Peacock; Christian Gieger; Marian Beekman; P Eline Slagboom; Joris Deelen; Diana van Heemst; Marcus E Kleber; Winfried Marz; 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 Joshi; James 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 Farrington; Maria Timofeeva; Malcolm Dunlop; Ana M. Valdes; Emmi Tikkanen; Terho Lehtimaki; Leo-Pekka Lyytikäinen; Mika Kahonen; Olli T. Raitakari; Vera Mikkila; 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 D. Spector; Thomas J. Wang; Elina Hypponen; 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 Jing, Paul F. O'Reilly, Hugues Aschard, Yi-Hsiang Hsu, J. Brent Richards, Josée Dupuis, Erik Ingelsson, David Karasik, Stefan Pilz, Diane J Berry, Bryan Kestenbaum, Jusheng Zheng, Jian'an Luan, Eleni Sofianopoulou, Elizabeth A Streeten, Demetrius Albanes, Pamela L. Lutsey, Lu Yao, Weihong Tang, Michael J. EconsHenri Wallaschofski, Henry Volzke, 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 W Enneman, L. Adrienne Cupples, Sarah L. Booth, Ramachandran S. Vasan, Ching-Ti Liu, Yanhua Zhou, Samuli Ripatti, Claes Ohlsson, Liesbeth Vandenput, Mattias Lorentzon, Johan Eriksson, M Kyla Shea, Denise K Houston, Stephen B. Kritchevsky, Yongmei Liu, Kurt Lohman, Luigi Ferrucci, Munro Peacock, Christian Gieger, Marian Beekman, P Eline Slagboom, Joris Deelen, Diana van Heemst, Marcus E Kleber, Winfried Marz, 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 Joshi, James 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 Farrington, Maria Timofeeva, Malcolm Dunlop, Ana M. Valdes, Emmi Tikkanen, Terho Lehtimaki, Leo-Pekka Lyytikäinen, Mika Kahonen, Olli T. Raitakari, Vera Mikkila, 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 D. Spector, Thomas J. Wang, Elina Hypponen, Peter Kraft, Douglas P Kiel

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

Abstract / Description of output

Vitamin D is an essential fat soluble vitamin and steroid pro-hormone that plays an important role in musculoskeletal health. Vitamin D deficiency has been linked to autoimmune1,2 and infectious disease3, cardiovascular disease4, cancer5 and neurodegenerative conditions6. Serum 25-hydroxyvitamin D, a primary circulating form of vitamin D and a measure that best reflects vitamin D stores, is influenced by many factors including sun exposure, age, body mass index7, dietary intake of certain foods such as fortified dairy products and oily fish, supplements, and genetic factors8. The concentration of 25-hydroxyvitamin D has been reported to be highly heritable, with heritability estimates of 50%-80% from classical twin studies9,10.
A genome-wide association study (GWAS) meta-analysis of serum 25-hydroxyvitamin D11 in 4,501 participants of European ancestry and replication in 2,221 samples identified variants in three loci (group component (GC), 7-dehydrochlesterol reductase (NADSYN1/DHCR7), and 25-hydroxylase (CYP2R1)). A larger GWAS conducted by the SUNLIGHT consortium in 16,125 European ancestry individuals, with a replication sample of 17,871, replicated these three loci and discovered one additional locus (CYP24A1)8. However, despite these loci being in or near genes encoding proteins involved in vitamin D synthesis, the associated variants collectively explain only a small fraction of the variance in 25-hydroxyvitamin D concentrations (~5%)8,11,12. Therefore, to extend our previous findings and better understand the genetic architecture underlying serum 25-hydroxyvitamin D, as well as test for interactions between dietary vitamin D intake and genetic factors, we conducted a large-scale GWAS meta-analysis on this important vitamin.
Our GWAS with 79,366 discovery samples and 40,562 replication samples replicate four previous loci and identify two new genetic loci for serum levels of 25-hydrovxyvitamin D. We further find evidence for a shared genetic basis between circulating 25-hydroxyvitamin D and autoimmune diseases. Our analyses suggest a relatively modest SNP-heritability rate of 25-hydroxyvitamin D when considering only common variants. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants. The novel genetic instruments identified by our results could be used in future Mendelian Randomization analyses of the association between vitamin D and complex traits

Original language	English
Journal	Nature Communications
Early online date	17 Jan 2018
DOIs	https://doi.org/:10.1038/s41467-017-02662-2
Publication status	E-pub ahead of print - 17 Jan 2018

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:10.1038/s41467-017-02662-2

Genome-wide association study in 79,366Final published version, 1.13 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

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Jing, X., O'Reilly, P. F., Aschard, H., Hsu, Y.-H., Richards, J. B., Dupuis, J., Ingelsson, E., Karasik, D., Pilz, S., Berry, D. J., 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. Advance online publication. https://doi.org/:10.1038/s41467-017-02662-2

@article{cff8c65238c64ff7aec323d500587834,

title = "Genome-wide Association Study in 79,366 European-ancestry Individuals Informs the Genetic Architecture of 25-Hydroxyvitamin D Levels",

abstract = "Vitamin D is an essential fat soluble vitamin and steroid pro-hormone that plays an important role in musculoskeletal health. Vitamin D deficiency has been linked to autoimmune1,2 and infectious disease3, cardiovascular disease4, cancer5 and neurodegenerative conditions6. Serum 25-hydroxyvitamin D, a primary circulating form of vitamin D and a measure that best reflects vitamin D stores, is influenced by many factors including sun exposure, age, body mass index7, dietary intake of certain foods such as fortified dairy products and oily fish, supplements, and genetic factors8. The concentration of 25-hydroxyvitamin D has been reported to be highly heritable, with heritability estimates of 50%-80% from classical twin studies9,10.A genome-wide association study (GWAS) meta-analysis of serum 25-hydroxyvitamin D11 in 4,501 participants of European ancestry and replication in 2,221 samples identified variants in three loci (group component (GC), 7-dehydrochlesterol reductase (NADSYN1/DHCR7), and 25-hydroxylase (CYP2R1)). A larger GWAS conducted by the SUNLIGHT consortium in 16,125 European ancestry individuals, with a replication sample of 17,871, replicated these three loci and discovered one additional locus (CYP24A1)8. However, despite these loci being in or near genes encoding proteins involved in vitamin D synthesis, the associated variants collectively explain only a small fraction of the variance in 25-hydroxyvitamin D concentrations (~5%)8,11,12. Therefore, to extend our previous findings and better understand the genetic architecture underlying serum 25-hydroxyvitamin D, as well as test for interactions between dietary vitamin D intake and genetic factors, we conducted a large-scale GWAS meta-analysis on this important vitamin. Our GWAS with 79,366 discovery samples and 40,562 replication samples replicate four previous loci and identify two new genetic loci for serum levels of 25-hydrovxyvitamin D. We further find evidence for a shared genetic basis between circulating 25-hydroxyvitamin D and autoimmune diseases. Our analyses suggest a relatively modest SNP-heritability rate of 25-hydroxyvitamin D when considering only common variants. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants. The novel genetic instruments identified by our results could be used in future Mendelian Randomization analyses of the association between vitamin D and complex traits",

author = "Xia Jing and O'Reilly, {Paul F.} and Hugues Aschard and Yi-Hsiang Hsu and Richards, {J. Brent} and Jos{\'e}e Dupuis and Erik Ingelsson and David Karasik and Stefan Pilz and Berry, {Diane J} and Bryan Kestenbaum and Jusheng Zheng and Jian'an 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 Volzke 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 Wen-Yi Huang and {van Schoor}, {Natasja M.} and {van der Velde}, Nathalie and {de Groot}, {Lisette C P G M} and Enneman, {Anke W} and {Adrienne Cupples}, L. and Booth, {Sarah L.} and Vasan, {Ramachandran S.} and Ching-Ti Liu and Yanhua Zhou and Samuli Ripatti and Claes Ohlsson and Liesbeth Vandenput and Mattias Lorentzon and Johan Eriksson and Shea, {M Kyla} and Houston, {Denise K} and Kritchevsky, {Stephen B.} and Yongmei Liu and Kurt Lohman and Luigi Ferrucci and Munro Peacock and Christian Gieger and Marian Beekman and Slagboom, {P Eline} and Joris Deelen and {van Heemst}, Diana and Kleber, {Marcus E} and Winfried Marz 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 Marjo-Riitta Jarvelin and Alana Cavadino and Peter Joshi and James Wilson 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 Susan Farrington and Maria Timofeeva and Malcolm Dunlop and Valdes, {Ana M.} and Emmi Tikkanen and Terho Lehtimaki and Leo-Pekka Lyytik{\"a}inen and Mika Kahonen and Raitakari, {Olli T.} and Vera Mikkila 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 Spector, {Timothy D.} and Wang, {Thomas J.} and Elina Hypponen and Peter Kraft and Kiel, {Douglas P}",

year = "2018",

month = jan,

day = "17",

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

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Jing, X, O'Reilly, PF, Aschard, H, Hsu, Y-H, Richards, JB, Dupuis, J, Ingelsson, E, Karasik, D, Pilz, S, Berry, DJ, Kestenbaum, B, Zheng, J, Luan, J, Sofianopoulou, E, Streeten, EA, Albanes, D, Lutsey, PL, Yao, L, Tang, W, Econs, MJ, Wallaschofski, H, Volzke, H, Zhou, A, Power, C, McCarthy, MI, Michos, ED, Boerwinkle, E, Weinstein, SJ, Freedman, ND, Huang, W-Y, van Schoor, NM, van der Velde, N, de Groot, LCPGM, Enneman, AW, Adrienne Cupples, L, Booth, SL, Vasan, RS, Liu, C-T, Zhou, Y, Ripatti, S, Ohlsson, C, Vandenput, L, Lorentzon, M, Eriksson, J, Shea, MK, Houston, DK, Kritchevsky, SB, Liu, Y, Lohman, K, Ferrucci, L, Peacock, M, Gieger, C, Beekman, M, Slagboom, PE, Deelen, J, van Heemst, D, Kleber, ME, Marz, W, de Boer, IH, Wood, AC, Rotter, JI, Rich, SS, Robinson-Cohen, C, den Heijer, M, Jarvelin, M-R, Cavadino, A, Joshi, P, Wilson, J , Hayward, C, Lind, L, Michaëlsson, K, Trompet, S, Zillikens, MC, Uitterlinden, AG, Rivadeneira, F, Broer, L, Zgaga, L, Campbell, H , Theodoratou, E , Farrington, S, Timofeeva, M, Dunlop, M, Valdes, AM, Tikkanen, E, Lehtimaki, T, Lyytikäinen, L-P, Kahonen, M, Raitakari, OT, Mikkila, V, Ikram, MA, Sattar, N, Jukema, JW, Wareham, NJ, Langenberg, C, Forouhi, NG, Gundersen, TE, Khaw, KT, Butterworth, AS, Danesh, J, Spector, TD, Wang, TJ, Hypponen, 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. https://doi.org/:10.1038/s41467-017-02662-2

TY - JOUR

T1 - Genome-wide Association Study in 79,366 European-ancestry Individuals Informs the Genetic Architecture of 25-Hydroxyvitamin D Levels

AU - Jing, 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 J

AU - Kestenbaum, Bryan

AU - Zheng, Jusheng

AU - Luan, Jian'an

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 - Volzke, 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 - de Groot, Lisette C P G M

AU - Enneman, Anke W

AU - Adrienne Cupples, L.

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

AU - Shea, M Kyla

AU - Houston, Denise K

AU - Kritchevsky, Stephen B.

AU - Liu, Yongmei

AU - Lohman, Kurt

AU - Ferrucci, Luigi

AU - Peacock, Munro

AU - Gieger, Christian

AU - Beekman, Marian

AU - Slagboom, P Eline

AU - Deelen, Joris

AU - van Heemst, Diana

AU - Kleber, Marcus E

AU - Marz, 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

AU - Wilson, James

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

AU - Timofeeva, Maria

AU - Dunlop, Malcolm

AU - Valdes, Ana M.

AU - Tikkanen, Emmi

AU - Lehtimaki, Terho

AU - Lyytikäinen, Leo-Pekka

AU - Kahonen, Mika

AU - Raitakari, Olli T.

AU - Mikkila, 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 D.

AU - Wang, Thomas J.

AU - Hypponen, Elina

AU - Kraft, Peter

AU - Kiel, Douglas P

PY - 2018/1/17

Y1 - 2018/1/17

N2 - Vitamin D is an essential fat soluble vitamin and steroid pro-hormone that plays an important role in musculoskeletal health. Vitamin D deficiency has been linked to autoimmune1,2 and infectious disease3, cardiovascular disease4, cancer5 and neurodegenerative conditions6. Serum 25-hydroxyvitamin D, a primary circulating form of vitamin D and a measure that best reflects vitamin D stores, is influenced by many factors including sun exposure, age, body mass index7, dietary intake of certain foods such as fortified dairy products and oily fish, supplements, and genetic factors8. The concentration of 25-hydroxyvitamin D has been reported to be highly heritable, with heritability estimates of 50%-80% from classical twin studies9,10.A genome-wide association study (GWAS) meta-analysis of serum 25-hydroxyvitamin D11 in 4,501 participants of European ancestry and replication in 2,221 samples identified variants in three loci (group component (GC), 7-dehydrochlesterol reductase (NADSYN1/DHCR7), and 25-hydroxylase (CYP2R1)). A larger GWAS conducted by the SUNLIGHT consortium in 16,125 European ancestry individuals, with a replication sample of 17,871, replicated these three loci and discovered one additional locus (CYP24A1)8. However, despite these loci being in or near genes encoding proteins involved in vitamin D synthesis, the associated variants collectively explain only a small fraction of the variance in 25-hydroxyvitamin D concentrations (~5%)8,11,12. Therefore, to extend our previous findings and better understand the genetic architecture underlying serum 25-hydroxyvitamin D, as well as test for interactions between dietary vitamin D intake and genetic factors, we conducted a large-scale GWAS meta-analysis on this important vitamin. Our GWAS with 79,366 discovery samples and 40,562 replication samples replicate four previous loci and identify two new genetic loci for serum levels of 25-hydrovxyvitamin D. We further find evidence for a shared genetic basis between circulating 25-hydroxyvitamin D and autoimmune diseases. Our analyses suggest a relatively modest SNP-heritability rate of 25-hydroxyvitamin D when considering only common variants. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants. The novel genetic instruments identified by our results could be used in future Mendelian Randomization analyses of the association between vitamin D and complex traits

AB - Vitamin D is an essential fat soluble vitamin and steroid pro-hormone that plays an important role in musculoskeletal health. Vitamin D deficiency has been linked to autoimmune1,2 and infectious disease3, cardiovascular disease4, cancer5 and neurodegenerative conditions6. Serum 25-hydroxyvitamin D, a primary circulating form of vitamin D and a measure that best reflects vitamin D stores, is influenced by many factors including sun exposure, age, body mass index7, dietary intake of certain foods such as fortified dairy products and oily fish, supplements, and genetic factors8. The concentration of 25-hydroxyvitamin D has been reported to be highly heritable, with heritability estimates of 50%-80% from classical twin studies9,10.A genome-wide association study (GWAS) meta-analysis of serum 25-hydroxyvitamin D11 in 4,501 participants of European ancestry and replication in 2,221 samples identified variants in three loci (group component (GC), 7-dehydrochlesterol reductase (NADSYN1/DHCR7), and 25-hydroxylase (CYP2R1)). A larger GWAS conducted by the SUNLIGHT consortium in 16,125 European ancestry individuals, with a replication sample of 17,871, replicated these three loci and discovered one additional locus (CYP24A1)8. However, despite these loci being in or near genes encoding proteins involved in vitamin D synthesis, the associated variants collectively explain only a small fraction of the variance in 25-hydroxyvitamin D concentrations (~5%)8,11,12. Therefore, to extend our previous findings and better understand the genetic architecture underlying serum 25-hydroxyvitamin D, as well as test for interactions between dietary vitamin D intake and genetic factors, we conducted a large-scale GWAS meta-analysis on this important vitamin. Our GWAS with 79,366 discovery samples and 40,562 replication samples replicate four previous loci and identify two new genetic loci for serum levels of 25-hydrovxyvitamin D. We further find evidence for a shared genetic basis between circulating 25-hydroxyvitamin D and autoimmune diseases. Our analyses suggest a relatively modest SNP-heritability rate of 25-hydroxyvitamin D when considering only common variants. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants. The novel genetic instruments identified by our results could be used in future Mendelian Randomization analyses of the association between vitamin D and complex traits

U2 - :10.1038/s41467-017-02662-2

DO - :10.1038/s41467-017-02662-2

M3 - Article

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -

Genome-wide Association Study in 79,366 European-ancestry Individuals Informs the Genetic Architecture of 25-Hydroxyvitamin D Levels

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