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

被引:294
作者
Jiang, Xia [1 ,2 ]
O'Reilly, Paul F. [3 ]
Aschard, Hugues [1 ,4 ]
Hsu, Yi-Hsiang [5 ,6 ,7 ,8 ]
Richards, J. Brent [9 ,10 ,11 ,12 ]
Dupuis, Josee [13 ,14 ]
Ingelsson, Erik [15 ,16 ]
Karasik, David [5 ]
Pilz, Stefan [17 ]
Berry, Diane [18 ]
Kestenbaum, Bryan [19 ]
Zheng, Jusheng [20 ]
Luan, Jianan [20 ]
Sofianopoulou, Eleni [21 ]
Streeten, Elizabeth A. [22 ]
Albanes, Demetrius [23 ]
Lutsey, Pamela L. [24 ]
Yao, Lu [24 ]
Tang, Weihong [24 ]
Econs, Michael J. [25 ]
Wallaschofski, Henri [26 ,27 ]
Voelzke, Henry [27 ,28 ]
Zhou, Ang [29 ]
Power, Chris [18 ]
McCarthy, Mark I. [30 ,31 ,32 ]
Michos, Erin D. [33 ,34 ]
Boerwinkle, Eric [35 ]
Weinstein, Stephanie J. [23 ]
Freedman, Neal D. [23 ]
Huang, Wen-Yi [36 ]
Van Schoor, Natasja M. [37 ]
van der Velde, Nathalie [38 ,39 ]
de Groot, Lisette C. P. G. M. [40 ]
Enneman, Anke [38 ]
Cupples, L. Adrienne [13 ,14 ]
Booth, Sarah L. [41 ]
Vasan, Ramachandran S. [14 ]
Liu, Ching-Ti [13 ]
Zhou, Yanhua [13 ]
Ripatti, Samuli [42 ]
Ohlsson, Claes [43 ]
Vandenput, Liesbeth [43 ]
Lorentzon, Mattias [44 ,45 ]
Eriksson, Johan G. [46 ,47 ,48 ]
Shea, M. Kyla [41 ]
Houston, Denise K. [49 ]
Kritchevsky, Stephen B. [49 ]
Liu, Yongmei [50 ]
Lohman, Kurt K. [51 ]
Ferrucci, Luigi [52 ]
机构
[1] Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, 677 Huntington Ave, Boston, MA USA
[2] Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Nobels Vagen 13, S-17177 Stockholm, Sweden
[3] Kings Coll London, Inst Psychiat, Dept Social Genet & Dev Psychiat, De Crespigny Pk, London SE5 8AF, England
[4] Inst Pasteur, Ctr Bioinformat Biostat & Biol Integrat C3BI, F-75724 Paris, France
[5] Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA
[6] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA
[7] Harvard Med Sch, Boston, MA 02115 USA
[8] Broad Inst Harvard & Massachusetts Inst Technol, Boston, MA 02142 USA
[9] Dept Med, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada
[10] Dept Human Genet, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada
[11] Dept Epidemiol, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada
[12] Dept Biostat, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada
[13] Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA
[14] Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA
[15] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA
[16] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden
[17] Med Univ Graz, Div Endocrinol & Diabetol, Dept Internal Med, Auenbruggerpl 15, A-8036 Graz, Austria
[18] UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England
[19] Kidney Res Inst, Div Nephrol, 325 Ninth Ave, Seattle, WA 98104 USA
[20] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England
[21] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England
[22] Univ Maryland, Genet & Personalized Med Program, Sch Med, Howard Hall Room 567, Baltimore, MD 21201 USA
[23] NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA
[24] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300S 2nd St,Suite 300, Minneapolis, MN 55454 USA
[25] Indiana Univ, Dept Med, Endocrinol, 1120W Michigan St, Indianapolis, IN 46202 USA
[26] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17489 Greifswald, Germany
[27] DZHK German Ctr Cardiovasc Res, Partner Site, D-13316 Greifswald, Germany
[28] Univ Med Greifswald, Inst Community Med, SHIP Klinisch Epidemiol Forsch, Walther Rathenau Str 48, D-17475 Greifswald, Germany
[29] Univ South Australia, Ctr Populat Hlth Res, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia
[30] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England
[31] Univ Oxford, Wellcome Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England
[32] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Old Rd, Oxford OX3 7LJ, England
[33] Johns Hopkins Sch Med, Ciccarone Ctr Prevent Heart Dis, Div Cardiol, Baltimore, MD 21287 USA
[34] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA
[35] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA
[36] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA
[37] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam Publ Hlth Res Inst, Boelelaan 1089a, NL-1081 HV Amsterdam, Netherlands
[38] Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands
[39] AMC, Internal Med, Dept Geriatr, POB 22700, NL-1100 DE Amsterdam, Netherlands
[40] Wageningen Univ, Dept Human Nutr, POB 176700, NL-6708 AA Wageningen, Netherlands
[41] Tufts Univ, Vitamin K Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA
[42] Univ Helsinki, Stat & Translat Genet, Biomedicum, Tukholmankatu 8, Helsinki 2U, Finland
[43] Univ Gothenburg, Dept Internal Med & Clin Nutr, Vita Straket 11, S-41345 Gothenburg, Sweden
[44] Univ Gothenburg, Dept Geriatr Med, S-43180 Molndal, Sweden
[45] Sahlgrens Univ Hosp, S-43180 Molndal, Sweden
[46] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, POB 20,Tukholmankatu 8 B, FIN-00014 Helsinki, Finland
[47] Univ Helsinki, Helsinki Univ Hosp, POB 20,Tukholmankatu 8 B, FIN-00014 Helsinki, Finland
[48] Univ Helsinki, Folkhalsan Res Ctr, POB 2000014, Helsinki, Finland
[49] Wake Forest Sch Med, Sticht Ctr Healthy Aging & Alzheimers Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA
[50] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA
来源
NATURE COMMUNICATIONS | 2018年 / 9卷
基金
英国医学研究理事会;
关键词
VITAMIN-D LEVELS; LENTICULO-SUTURAL DYSPLASIA; PARTITIONING HERITABILITY; MULTIPLE-SCLEROSIS; ADOLESCENT TWINS; CELL-TYPES; RISK LOCI; VARIANTS; DISEASE; METAANALYSIS;
D O I
10.1038/s41467-017-02662-2
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 = 4.7x10(-9) at rs8018720 in SEC23A, and P = 1.9x10(-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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页数:12
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