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 Econs & 84 others 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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 languageEnglish (US)
Article number260
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

genome
Genome-Wide Association Study
loci
Genes
genes
serums
calciferol
Single Nucleotide Polymorphism
steroids
hormones
Steroid hormones
descent
Genome
Serum
Vitamin D
Sample Size
Autoimmune Diseases
Cluster Analysis
Steroids
Hormones

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. / Jiang, Xia; O'Reilly, Paul F.; Aschard, Hugues; Hsu, Yi Hsiang; Richards, J. Brent; Dupuis, Josée; Ingelsson, Erik; Karasik, David; Pilz, Stefan; Berry, DIane; Kestenbaum, Bryan; Zheng, Jusheng; Luan, Jianan; Sofianopoulou, Eleni; Streeten, Elizabeth A.; Albanes, Demetrius; Lutsey, Pamela L.; Yao, Lu; Tang, Weihong; Econs, Michael; Wallaschofski, Henri; Völzke, Henry; Zhou, Ang; Power, Chris; McCarthy, Mark I.; Michos, Erin D.; Boerwinkle, Eric; Weinstein, Stephanie J.; Freedman, Neal D.; Huang, Wen Yi; Van Schoor, Natasja M.; Van Der Velde, Nathalie; Groot, Lisette C.P.G.M.De; Enneman, Anke; Cupples, L. Adrienne; Booth, Sarah L.; Vasan, Ramachandran S.; Liu, Ching Ti; Zhou, Yanhua; Ripatti, Samuli; Ohlsson, Claes; Vandenput, Liesbeth; Lorentzon, Mattias; Eriksson, Johan G.; Shea, M. Kyla; Houston, Denise K.; Kritchevsky, Stephen B.; Liu, Yongmei; Lohman, Kurt K.; Ferrucci, Luigi; Peacock, Munro; Gieger, Christian; Beekman, Marian; Slagboom, Eline; Deelen, Joris; Heemst, DIana Van; Kleber, Marcus E.; März, Winfried; De Boer, Ian H.; Wood, Alexis C.; Rotter, Jerome I.; Rich, Stephen S.; Robinson-Cohen, Cassianne; Den Heijer, Martin; Jarvelin, Marjo Riitta; Cavadino, Alana; Joshi, Peter K.; Wilson, James F.; Hayward, Caroline; Lind, Lars; Michaëlsson, Karl; Trompet, Stella; Zillikens, M. Carola; Uitterlinden, Andre G.; Rivadeneira, Fernando; Broer, Linda; Zgaga, Lina; Campbell, Harry; Theodoratou, Evropi; Farrington, Susan M.; Timofeeva, Maria; Dunlop, Malcolm G.; Valdes, Ana M.; Tikkanen, Emmi; Lehtimäki, Terho; Lyytikäinen, Leo Pekka; Kähönen, Mika; Raitakari, Olli T.; Mikkilä, Vera; Ikram, M. Arfan; Sattar, Naveed; Jukema, J. Wouter; Wareham, Nicholas J.; Langenberg, Claudia; Forouhi, Nita G.; Gundersen, Thomas E.; Khaw, Kay Tee; Butterworth, Adam S.; Danesh, John; Spector, Timothy; Wang, Thomas J.; Hyppönen, Elina; Kraft, Peter; Kiel, Douglas P.

In: Nature Communications, Vol. 9, No. 1, 260, 01.12.2018.

Research output: Contribution to journalArticle

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, M, 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
Jiang, Xia ; O'Reilly, Paul F. ; Aschard, Hugues ; Hsu, Yi Hsiang ; Richards, J. Brent ; Dupuis, Josée ; Ingelsson, Erik ; Karasik, David ; Pilz, Stefan ; Berry, DIane ; Kestenbaum, Bryan ; Zheng, Jusheng ; Luan, Jianan ; Sofianopoulou, Eleni ; Streeten, Elizabeth A. ; Albanes, Demetrius ; Lutsey, Pamela L. ; Yao, Lu ; Tang, Weihong ; Econs, Michael ; Wallaschofski, Henri ; Völzke, Henry ; Zhou, Ang ; Power, Chris ; McCarthy, Mark I. ; Michos, Erin D. ; Boerwinkle, Eric ; Weinstein, Stephanie J. ; Freedman, Neal D. ; Huang, Wen Yi ; Van Schoor, Natasja M. ; Van Der Velde, Nathalie ; Groot, Lisette C.P.G.M.De ; Enneman, Anke ; Cupples, L. Adrienne ; Booth, Sarah L. ; Vasan, Ramachandran S. ; Liu, Ching Ti ; Zhou, Yanhua ; Ripatti, Samuli ; Ohlsson, Claes ; Vandenput, Liesbeth ; Lorentzon, Mattias ; Eriksson, Johan G. ; Shea, M. Kyla ; Houston, Denise K. ; Kritchevsky, Stephen B. ; Liu, Yongmei ; Lohman, Kurt K. ; Ferrucci, Luigi ; Peacock, Munro ; Gieger, Christian ; Beekman, Marian ; Slagboom, Eline ; Deelen, Joris ; Heemst, DIana Van ; Kleber, Marcus E. ; März, Winfried ; De Boer, Ian H. ; Wood, Alexis C. ; Rotter, Jerome I. ; Rich, Stephen S. ; Robinson-Cohen, Cassianne ; Den Heijer, Martin ; Jarvelin, Marjo Riitta ; Cavadino, Alana ; Joshi, Peter K. ; Wilson, James F. ; Hayward, Caroline ; Lind, Lars ; Michaëlsson, Karl ; Trompet, Stella ; Zillikens, M. Carola ; Uitterlinden, Andre G. ; Rivadeneira, Fernando ; Broer, Linda ; Zgaga, Lina ; Campbell, Harry ; Theodoratou, Evropi ; Farrington, Susan M. ; Timofeeva, Maria ; Dunlop, Malcolm G. ; Valdes, Ana M. ; Tikkanen, Emmi ; Lehtimäki, Terho ; Lyytikäinen, Leo Pekka ; Kähönen, Mika ; Raitakari, Olli T. ; Mikkilä, Vera ; Ikram, M. Arfan ; Sattar, Naveed ; Jukema, J. Wouter ; Wareham, Nicholas J. ; Langenberg, Claudia ; Forouhi, Nita G. ; Gundersen, Thomas E. ; Khaw, Kay Tee ; Butterworth, Adam S. ; Danesh, John ; Spector, Timothy ; Wang, Thomas J. ; Hyppönen, Elina ; Kraft, Peter ; Kiel, Douglas P. / Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.",
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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

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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JO - Nature Communications

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