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.B. 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 & 58 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.A. Cupples, Sarah L. Booth, Ramachandran S. Vasan, Ching Ti Liu, Yanhua Zhou, Samuli Ripatti, Claes Ohlsson, Liesbeth Vandenput, Mattias Lorentzon, Johan G. Eriksson, M.K. Shea, Denise K. Houston, Stephen B. Kritchevsky, Yongmei Liu, Kurt K. Lohman, Luigi Ferrucci, Munro Peacock, Christian Gieger, Marian Beekman, Eline Slagboom, Joris Deelen, 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, Marjo Riitta Jarvelin, Alana Cavadino, Alana Cavadino, Peter K. Joshi, James F. Wilson, Caroline Hayward, Lars Lind, Karl Michaëlsson, Stella Trompet, M.C. Zillikens, Andre G. Uitterlinden, Fernando Rivadeneira

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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.
LanguageEnglish
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 17 Jan 2018

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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

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Jiang, Xia ; O'Reilly, Paul F. ; Aschard, Hugues ; Hsu, Yi Hsiang ; Richards, J.B. ; 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 J. ; 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 ; de Groot, Lisette C.P.G.M. ; Enneman, Anke ; Cupples, L.A. ; Booth, Sarah L. ; Vasan, Ramachandran S. ; Liu, Ching Ti ; Zhou, Yanhua ; Ripatti, Samuli ; Ohlsson, Claes ; Vandenput, Liesbeth ; Lorentzon, Mattias ; Eriksson, Johan G. ; Shea, M.K. ; Houston, Denise K. ; Kritchevsky, Stephen B. ; Liu, Yongmei ; Lohman, Kurt K. ; Ferrucci, Luigi ; Peacock, Munro ; Gieger, Christian ; Beekman, Marian ; Slagboom, Eline ; Deelen, Joris ; Deelen, Joris ; van Heemst, Diana ; 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 ; Jarvelin, Marjo Riitta ; Cavadino, Alana ; Cavadino, Alana ; Joshi, Peter K. ; Wilson, James F. ; Hayward, Caroline ; Lind, Lars ; Michaëlsson, Karl ; Trompet, Stella ; Zillikens, M.C. ; Uitterlinden, Andre G. ; Rivadeneira, Fernando. / 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.
@article{acd34905fe28475e85fad148cd79e570,
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 J.B. Richards 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 {de Groot}, {Lisette C.P.G.M.} and Anke Enneman and L.A. Cupples 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 M.K. Shea 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 Joris Deelen and {van Heemst}, Diana 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 Jarvelin, {Marjo Riitta} and Alana Cavadino 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 M.C. Zillikens and Uitterlinden, {Andre G.} and Fernando Rivadeneira",
year = "2018",
month = "1",
day = "17",
doi = "10.1038/s41467-017-02662-2",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
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Jiang, X, O'Reilly, PF, Aschard, H, Hsu, YH, Richards, JB, Dupuis, J, Ingelsson, E, Karasik, D, Pilz, S, Berry, D, 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, de Groot, LCPGM, 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, Deelen, J, van Heemst, D, Kleber, ME, März, W, De Boer, IH, Wood, AC, Rotter, JI, Rich, SS, Robinson-Cohen, C, Den Heijer, M, Jarvelin, MR, Jarvelin, MR, Cavadino, A, Cavadino, A, Joshi, PK, Wilson, JF, Hayward, C, Lind, L, Michaëlsson, K, Trompet, S, Zillikens, MC, Uitterlinden, AG & Rivadeneira, F 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. https://doi.org/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. / Jiang, Xia; O'Reilly, Paul F.; Aschard, Hugues; Hsu, Yi Hsiang; Richards, J.B.; 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 J.; 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; de Groot, Lisette C.P.G.M.; Enneman, Anke; Cupples, L.A.; Booth, Sarah L.; Vasan, Ramachandran S.; Liu, Ching Ti; Zhou, Yanhua; Ripatti, Samuli; Ohlsson, Claes; Vandenput, Liesbeth; Lorentzon, Mattias; Eriksson, Johan G.; Shea, M.K.; Houston, Denise K.; Kritchevsky, Stephen B.; Liu, Yongmei; Lohman, Kurt K.; Ferrucci, Luigi; Peacock, Munro; Gieger, Christian; Beekman, Marian; Slagboom, Eline; Deelen, Joris; Deelen, Joris; van Heemst, Diana; 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; Jarvelin, Marjo Riitta; Cavadino, Alana; Cavadino, Alana; Joshi, Peter K.; Wilson, James F.; Hayward, Caroline; Lind, Lars; Michaëlsson, Karl; Trompet, Stella; Zillikens, M.C.; Uitterlinden, Andre G.; Rivadeneira, Fernando.

In: Nature Communications, Vol. 9, No. 1, 17.01.2018.

Research output: Contribution to journalArticleAcademicpeer-review

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.B.

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

AU - Enneman, Anke

AU - Cupples, L.A.

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.K.

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 - Deelen, Joris

AU - van Heemst, Diana

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 - Jarvelin, Marjo Riitta

AU - Cavadino, Alana

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.C.

AU - Uitterlinden, Andre G.

AU - Rivadeneira, Fernando

PY - 2018/1/17

Y1 - 2018/1/17

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.

U2 - 10.1038/s41467-017-02662-2

DO - 10.1038/s41467-017-02662-2

M3 - Article

VL - 9

JO - Nature Communications

T2 - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

ER -