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

Nature Communications

Volumn 9, Issue 1, 2018, Pages

  Jiang, Xia ^a,b   O'Reilly, Paul F ^c   Aschard, Hugues ^a,d   Hsu, Yi Hsiang ^e,f,g   Richards, J Brent ^h   Dupuis, Josée ^i,j   Ingelsson, Erik ^k,l   Karasik, David ^e   Pilz, Stefan ^m   Berry, DIane ⁿ   Kestenbaum, Bryan ^o   Zheng, Jusheng ^p   Luan, Jianan ^p   Sofianopoulou, Eleni ^q   Streeten, Elizabeth A ^r   Albanes, Demetrius ^s   Lutsey, Pamela L ^t   Yao, Lu ^t   Tang, Weihong ^t   Econs, Michael J ^u   Wallaschofski, Henri ^v,w   Völzke, Henry ^v,w   Zhou, Ang ^x   Power, Chris ⁿ   McCarthy, Mark I ^y,z,aa   Michos, Erin D ^ab,ac   Boerwinkle, Eric ^ad   Weinstein, Stephanie J ^s   Freedman, Neal D ^s   Huang, Wen Yi ^s   Van Schoor, Natasja M ^ae   Van Der Velde, Nathalie ^af,ag   Groot, Lisette C P G M De ^ah   Enneman, Anke ^af   Cupples, L Adrienne ^i,j   Booth, Sarah L ^ai   Vasan, Ramachandran S ^j   Liu, Ching Ti ⁱ   Zhou, Yanhua ⁱ   Ripatti, Samuli ^aj   Ohlsson, Claes ^ak   Vandenput, Liesbeth ^ak   Lorentzon, Mattias ^al   Eriksson, Johan G ^aj   Shea, M Kyla ^ai   Houston, Denise K ^am   Kritchevsky, Stephen B ^am   Liu, Yongmei ^am   Lohman, Kurt K ^am   Ferrucci, Luigi ^an   Peacock, Munro ^u   Gieger, Christian ^ao   Beekman, Marian ^ap   Slagboom, Eline ^ap   Deelen, Joris ^ap,aq   Heemst, DIana Van ^ap   Kleber, Marcus E ^ar   März, Winfried ^m,ar,as   De Boer, Ian H ^at   Wood, Alexis C ^au   Rotter, Jerome I ^av   Rich, Stephen S ^aw,ax   Robinson Cohen, Cassianne ^ay   Den Heijer, Martin ^af   Jarvelin, Marjo Riitta ^az,ba,bb,bc   Cavadino, Alana ^n,bd   Joshi, Peter K ^be   Wilson, James F ^be,bf   Hayward, Caroline ^bf   Lind, Lars ^l   Michaëlsson, Karl ^l   Trompet, Stella ^ap   Zillikens, M Carola ^af   Uitterlinden, Andre G ^af   Rivadeneira, Fernando ^af   Broer, Linda ^af   Zgaga, Lina ^bg   Campbell, Harry ^be,bh   Theodoratou, Evropi ^be,bh   Farrington, Susan M ^bh   Timofeeva, Maria ^bh   Dunlop, Malcolm G ^bh   Valdes, Ana M ^c,bi   Tikkanen, Emmi ^aj   Lehtimäki, Terho ^bj,bk   Lyytikäinen, Leo Pekka ^bj,bk   Kähönen, Mika ^bk,bl   Raitakari, Olli T ^bm,bn   Mikkilä, Vera ^bo   Ikram, M Arfan ^af   Sattar, Naveed ^bp   Jukema, J Wouter ^ap   Wareham, Nicholas J ^p   Langenberg, Claudia ^p   Forouhi, Nita G ^p   Gundersen, Thomas E ^bq   Khaw, Kay Tee ^q   Butterworth, Adam S ^q   Danesh, John ^q,br   Spector, Timothy ^c   Wang, Thomas J ^ay   Hyppönen, Elina ^n,x   Kraft, Peter ^a   Kiel, Douglas P ^e,f,g   more..

^a HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^b KAROLINSKA INSTITUTE   (Sweden)

^c KING'S COLLEGE LONDON   (United Kingdom)

^d INSTITUT PASTEUR   (France)

^e Hebrew Senior Life   (United States)

^f HARVARD MEDICAL SCHOOL   (United States)

^g MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^h Epidemiology and Biostatistics   (Canada)

ⁱ BOSTON UNIVERSITY   (United States)

^j FRAMINGHAM HEART STUDY   (United States)

^k STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^l UPPSALA UNIVERSITY   (Sweden)

^m MEDICAL UNIVERSITY OF GRAZ   (Austria)

ⁿ UNIVERSITY COLLEGE LONDON   (United Kingdom)

^o Division of Nephrology   (United States)

^p UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^q UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^r UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^s NATIONAL CANCER INSTITUTE   (United States)

^t UNIVERSITY OF MINNESOTA   (United States)

^u INDIANA UNIVERSITY   (United States)

^v UNIVERSITY MEDICINE GREIFSWALD   (Germany)

^w DZHK GERMAN CENTRE FOR CARDIOVASCULAR RESEARCH   (Germany)

^x UNIVERSITY OF SOUTH AUSTRALIA   (Australia)

^y UNIVERSITY OF OXFORD   (United Kingdom)

^z UNIVERSITY OF OXFORD   (United Kingdom)

^aa CHURCHILL HOSPITAL   (United Kingdom)

^ab JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^ac JOHNS HOPKINS UNIVERSITY   (United States)

^ad UNIVERSITY OF TEXAS   (United States)

^ae VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^af ERASMUS MEDICAL CENTER   (Netherlands)

^ag ACADEMIC MEDICAL CENTER   (Netherlands)

^ah WAGENINGEN UNIVERSITY   (Netherlands)

^ai TUFTS UNIVERSITY   (United States)

^aj UNIVERSITY OF HELSINKI   (Finland)

^ak UNIVERSITY OF GOTHENBURG   (Sweden)

^al SAHLGRENSKA UNIVERSITY HOSPITAL   (Sweden)

^am WAKE FOREST SCHOOL OF MEDICINE   (United States)

^an NATIONAL INSTITUTE ON AGING   (United States)

^ao INSTITUTE OF EPIDEMIOLOGY   (Germany)

^ap LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^aq MAX PLANCK INSTITUTE FOR BIOLOGY OF AGEING   (Germany)

^ar UNIVERSITY OF HEIDELBERG   (Germany)

^as SYNLAB ACADEMY   (Germany)

^at UNIVERSITY OF WASHINGTON   (United States)

^au CHILDREN S NUTRITION RESEARCH CENTER   (United States)

^av HARBOR UCLA MEDICAL CENTER   (United States)

^aw UNIVERSITY OF VIRGINIA   (United States)

^ax UNIVERSITY OF VIRGINIA   (United States)

^ay VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^az IMPERIAL COLLEGE LONDON   (United Kingdom)

^ba UNIVERSITY OF OULU   (Finland)

^bb UNIVERSITY OF OULU   (Finland)

^bc OULU UNIVERSITY HOSPITAL   (Finland)

^bd QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^be UNIVERSITY OF EDINBURGH   (United Kingdom)

^bf UNIVERSITY OF EDINBURGH   (United Kingdom)

^bg TRINITY COLLEGE DUBLIN   (Ireland)

^bh UNIVERSITY OF EDINBURGH   (United Kingdom)

^bi UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^bj FIMLAB LABORATORIES   (Finland)

^bk TAMPERE UNIVERSITY OF TECHNOLOGY   (Finland)

^bl TAMPERE UNIVERSITY HOSPITAL   (Finland)

^bm TURKU UNIVERSITY HOSPITAL   (Finland)

^bn UNIVERSITY OF TURKU   (Finland)

^bo ACADEMY OF FINLAND   (Finland)

^bp UNIVERSITY OF GLASGOW   (United Kingdom)

^bq Vitas as   (Norway)

^br WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

more..

Author keywords

[No Author keywords available]

Indexed keywords

25 HYDROXYVITAMIN D; AMDHD1 PROTEIN; COLECALCIFEROL 24 HYDROXYLASE; CYP2R1 PROTEIN; DHCR7 PROTEIN; NADSYN1 PROTEIN; PROTEIN; SEC23A PROTEIN; UNCLASSIFIED DRUG; 25-HYDROXYVITAMIN D; AMIDASE; SEC23A PROTEIN, HUMAN; VESICULAR TRANSPORT PROTEIN; VITAMIN D;

BLOOD; CONCENTRATION (COMPOSITION); GENE; GENETIC ANALYSIS; GENOME; HORMONE; IMMUNE RESPONSE; MUSCLE; VITAMIN;

ARTICLE; BONE TISSUE; CHROMATIN; CONTROLLED STUDY; ENHANCER REGION; GASTROINTESTINAL TISSUE; GENE INTERACTION; GENE LINKAGE DISEQUILIBRIUM; GENE LOCUS; GENETIC CORRELATION; GENOME-WIDE ASSOCIATION STUDY; HEMATOPOIETIC TISSUE; HERITABILITY; HUMAN; SINGLE NUCLEOTIDE POLYMORPHISM; VITAMIN BLOOD LEVEL; VITAMIN INTAKE; ANALOGS AND DERIVATIVES; AUTOIMMUNE DISEASE; BLOOD; CAUCASIAN; COHORT ANALYSIS; FEMALE; GENETICS; MALE;

AMIDOHYDROLASES; AUTOIMMUNE DISEASES; COHORT STUDIES; EUROPEAN CONTINENTAL ANCESTRY GROUP; FEMALE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; MALE; POLYMORPHISM, SINGLE NUCLEOTIDE; VESICULAR TRANSPORT PROTEINS; VITAMIN D;

EID: 85041401774     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/s41467-017-02662-2     Document Type: Article

References (56)

1. Mokry, L. E. et al. Vitamin D and risk of multiple sclerosis: A mendelian randomization study. PLoS Med. 12, e1001866 (2015).
2. Rhead, B. et al. Mendelian randomization shows a causal effect of low Vitamin D on multiple sclerosis risk. Neurol. Genet. 2, e97 (2016).
3. Martineau, A. R. et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. Br. Med. J. 356, i6583 (2017).
4. Pilz, S., Verheyen, N., Grübler, M. R., Tomaschitz, A. & März, W. Vitamin D and cardiovascular disease prevention. Nat. Rev. Cardiol. 13, 404-417 (2016).
5. Garland, C. F. et al. The role of Vitamin D in cancer prevention. Am. J. Public Health 96, 252-261 (2006).
6. Fernandes de Abreu, D. A., Eyles, D. & Féron, F. Vitamin D, a neuroimmunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology 34 Suppl 1, S265-277 (2009).
7. Lagunova, Z., Porojnicu, A. C., Lindberg, F., Hexeberg, S. & Moan, J. The dependency of Vitamin D status on body mass index, gender, age and season. Anticancer Res. 29, 3713-3720 (2009).
8. Wang, T. J. et al. Common genetic determinants of Vitamin D insufficiency: A genome-wide association study. Lancet Lond. Engl. 376, 180-188 (2010).
9. Karohl, C. et al. Heritability and seasonal variability of Vitamin D concentrations in male twins. Am. J. Clin. Nutr. 92, 1393-1398 (2010).
10. Orton, S.-M. et al. Evidence for genetic regulation of Vitamin D status in twins with multiple sclerosis. Am. J. Clin. Nutr. 88, 441-447 (2008).
11. Ahn, J. et al. Genome-wide association study of circulating Vitamin D levels. Hum. Mol. Genet. 19, 2739-2745 (2010).
12. Hiraki, L. T. et al. Exploring the genetic architecture of circulating 25-hydroxyVitamin D. Genet. Epidemiol. 37, 92-98 (2013).
13. Boyadjiev, S. et al. Cranio-lenticulo-sutural dysplasia associated with defects in collagen secretion. Clin. Genet. 80, 169-176 (2011).
14. Boyadjiev, S. A. et al. Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking. Nat. Genet. 38, 1192-1197 (2006).
15. Myung, J. K. et al. Well-differentiated liposarcoma of the oesophagus: clinicopathological, immunohistochemical and array CGH analysis. Pathol. Oncol. Res. 17, 415-420 (2011).
16. Manousaki, D. et al. Low-frequency synonymous coding variation in CYP2R1 has large effects on Vitamin D levels and risk of multiple sclerosis. Am. J. Hum. Genet. 101, 227-238 (2017).
17. Arguelles, L. M. et al. Heritability and environmental factors affecting Vitamin D status in rural Chinese adolescent twins. J. Clin. Endocrinol. Metab. 94, 3273-3281 (2009).
18. Mills, N. T. et al. Heritability of transforming growth factor-1 and tumor necrosis factor-receptor type 1 expression and Vitamin D levels in healthy adolescent twins. Twin Res. Hum. Genet. Off. J. Int. Soc. Twin Stud. 18, 28-35 (2015).
19. Livshits, G., Karasik, D. & Seibel, M. J. Statistical genetic analysis of plasma levels of Vitamin D: familial study. Ann. Hum. Genet. 63, 429-439 (1999).
20. Yu, H.-J., Kwon, M.-J., Woo, H.-Y. & Park, H. Analysis of 25-hydroxyVitamin D status according to age, gender, and seasonal variation. J. Clin. Lab. Anal. 30, 905-911 (2016).
21. Hunter, D. et al. Genetic contribution to bone metabolism, calcium excretion, and Vitamin D and parathyroid hormone regulation. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 16, 371-378 (2001).
22. Agmon-Levin, N., Theodor, E., Segal, R. M. & Shoenfeld, Y. Vitamin D in systemic and organ-specific autoimmune diseases. Clin. Rev. Allergy Immunol. 45, 256-266 (2013).
23. Yang, C.-Y., Leung, P. S. C., Adamopoulos, I. E. & Gershwin, M. E. The implication of Vitamin D and autoimmunity: A comprehensive review. Clin. Rev. Allergy Immunol. 45, 217-226 (2013).
24. Aschard, H. A perspective on interaction effects in genetic association studies. Genet. Epidemiol. 40, 678-688 (2016).
25. Cooper, J. D. et al. Inherited variation in Vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 60, 1624-1631 (2011).
26. Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinforma. Oxf. Engl. 26, 2190-2191 (2010).
27. Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369-375 (2012).
28. Aschard, H., Hancock, D. B., London, S. J. & Kraft, P. Genome-wide metaanalysis of joint tests for genetic and gene-environment interaction effects. Hum. Hered. 70, 292-300 (2010).
29. Manning, A. K. et al. Meta-analysis of gene-environment interaction: joint estimation of SNP and SNP×environment regression coefficients. Genet. Epidemiol. 35, 11-18 (2011).
30. Bulik-Sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291-295 (2015).
31. Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228-1235 (2015).
32. Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996-1006 (2002).
33. Gusev, A. et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535-552 (2014).
34. Roadmap Epigenomics Consortium. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317-330 (2015).
35. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74 (2012).
36. Trynka, G. et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat. Genet. 45, 124-130 (2013).
37. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934-947 (2013).
38. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421-427 (2014).
39. Hoffman, M. M. et al. Integrative annotation of chromatin elements from ENCODE data. Nucleic Acids Res. 41, 827-841 (2013).
40. Lindblad-Toh, K. et al. A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478, 476-482 (2011).
41. Ward, L. D. & Kellis, M. Evidence of abundant purifying selection in humans for recently acquired regulatory functions. Science 337, 1675-1678 (2012).
42. Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455-461 (2014).
43. Boraska, V. et al. A genome-wide association study of anorexia nervosa. Mol. Psychiatry 19, 1085-1094 (2014).
44. Global Lipids Genetics Consortium. et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274-1283 (2013).
45. Bentham, J. et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat. Genet. 47, 1457-1464 (2015).
46. Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376-381 (2014).
47. Okbay, A. et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat. Genet. 48, 624-633 (2016).
48. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124 (2012).
49. Cross-Disorder, Group of the Psychiatric Genomics Consortium Identification of risk loci with shared effects on five major psychiatric disorders: A genomewide analysis. Lancet Lond. Engl. 381, 1371-1379 (2013).
50. Cordell, H. J. et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat. Commun. 6, 8019 (2015).
51. Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333-338 (2011).
52. Morris, A. P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981-990 (2012).
53. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat. Genet. 43, 977-983 (2011).
54. Dubois, P. C. A. et al. Multiple common variants for celiac disease influencing immune gene expression. Nat. Genet. 42, 295-302 (2010).
55. Thorgeirsson, T. E. et al. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat. Genet. 42, 448-453 (2010).
56. Pickrell, J. K. et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48, 709-717 (2016).