Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

Nature Genetics

Volumn 48, Issue 5, 2016, Pages 510-518

  Ellinghaus, David ^a   Jostins, Luke ^b   Spain, Sarah L ^b   Cortes, Adrian ^c,d   Bethune, Jörn ^a   Han, Buhm ^e   Park, Yu Rang ^e   Raychaudhuri, Soumya ^f,g,h   Pouget, Jennie G ^i,j   Hübenthal, Matthias ^a   Folseraas, Trine ^k,l,m   Wang, Yunpeng ⁿ   Esko, Tonu ^o,p   Metspalu, Andres ^o   Westra, Harm Jan ^f,g,h   Franke, Lude ^q   Pers, Tune H ^f,p,r,s   Weersma, Rinse K ^q   Collij, Valerie ^q   D'Amato, Mauro ^t,u   Halfvarson, Jonas ^v   Jensen, Anders Boeck ^w   Lieb, Wolfgang ^x   Degenhardt, Franziska ^y   Forstner, Andreas J ^y   Hofmann, Andrea ^y   Schreiber, Stefan ^a,x   Mrowietz, Ulrich ^x   Juran, Brian D ^z   Lazaridis, Konstantinos N ^z   Brunak, SØren ^w   Dale, Anders M ^n,aa   Trembath, Richard C ^ab   Weidinger, Stephan ^x   Weichenthal, Michael ^x   Ellinghaus, Eva ^a   Elder, James T ^ac,ad   Barker, Jonathan N W N ^ab   Andreassen, Ole A ^l,ae   McGovern, Dermot P ^af,ag   Karlsen, Tom H ^k,l,m   Barrett, Jeffrey C ^b   Parkes, Miles ^ah   Brown, Matthew A ^ai,aj   Franke, Andre ^a   more..

^a UNIVERSITY OF KIEL   (Germany)

^b WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^c UNIVERSITY OF OXFORD   (United Kingdom)

^d UNIVERSITY OF OXFORD   (United Kingdom)

^e University of Ulsan   (South Korea)

^f BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^g BRIGHAM AND WOMEN S HOSPITAL   (United States)

^h HARVARD MEDICAL SCHOOL   (United States)

ⁱ CENTRE FOR ADDICTION AND MENTAL HEALTH   (Canada)

^j UNIVERSITY OF TORONTO   (Canada)

^k OSLO UNIVERSITY HOSPITAL   (Norway)

^l UNIVERSITY OF OSLO   (Norway)

^m OSLO UNIVERSITY HOSPITAL   (Norway)

ⁿ UNIVERSITY OF CALIFORNIA   (United States)

^o UNIVERSITY OF TARTU   (Estonia)

^p BOSTON CHILDREN S HOSPITAL   (United States)

^q UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^r UNIVERSITY OF COPENHAGEN   (Denmark)

^s STATENS SERUM INSTITUT   (Denmark)

^t KAROLINSKA INSTITUTE   (Sweden)

^u BASQUE FOUNDATION FOR SCIENCE   (Spain)

^v Örebro University   (Sweden)

^w University of Copenhagen   (Denmark)

^x UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^y UNIVERSITY OF BONN   (Germany)

^z MAYO CLINIC   (United States)

^aa UNIVERSITY OF CALIFORNIA   (United States)

^ab KING'S COLLEGE LONDON   (United Kingdom)

^ac UNIVERSITY OF MICHIGAN HEALTH SYSTEM   (United States)

^ad VETERANS AFFAIRS MEDICAL CENTER   (United States)

^ae ULLEVÅL UNIVERSITY HOSPITAL   (Norway)

^af F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute   (United States)

^ag CEDARS SINAI MEDICAL CENTER   (United States)

^ah UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^ai UNIVERSITY OF QUEENSLAND   (Australia)

^aj QUEENSLAND UNIVERSITY OF TECHNOLOGY   (Australia)

more..

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE RECRUITMENT DOMAIN PROTEIN 15; CD6 ANTIGEN; G PROTEIN COUPLED RECEPTOR 35; GLUCOKINASE REGULATORY PROTEIN; INTERFERON INDUCED WITH HELICASE C DOMAIN 1; NON RECEPTOR PROTEIN TYROSINE PHOSPHATASE 22; PROTEIN; PROTEIN CARD9; PROTEIN KINASE TYK2; PROTEIN MST1; PROTEIN SH2B3; SMAD3 PROTEIN; UNCLASSIFIED DRUG;

ANKYLOSING SPONDYLITIS; ARTICLE; CHRONIC DISEASE; COMORBIDITY; CONTROLLED STUDY; CROHN DISEASE; ENHANCER REGION; EPIGENETICS; EUROPEAN; GENE EXPRESSION; GENE LOCUS; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC HETEROGENEITY; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; GENOME-WIDE ASSOCIATION STUDY; GENOTYPE; HUMAN; IMMUNOPATHOLOGY; INFLAMMATORY DISEASE; MAJOR CLINICAL STUDY; PLEIOTROPY; PRIMARY SCLEROSING CHOLANGITIS; PRIORITY JOURNAL; PSORIASIS; QUANTITATIVE TRAIT LOCUS; ULCERATIVE COLITIS; BAYES THEOREM; GENETIC VARIATION; GENETICS; INFLAMMATION; SCLEROSING CHOLANGITIS;

BAYES THEOREM; CHOLANGITIS, SCLEROSING; CHRONIC DISEASE; COLITIS, ULCERATIVE; COMORBIDITY; CROHN DISEASE; GENETIC HETEROGENEITY; GENETIC PLEIOTROPY; GENETIC VARIATION; GENOME-WIDE ASSOCIATION STUDY; GENOTYPE; HUMANS; INFLAMMATION; PSORIASIS; QUANTITATIVE TRAIT LOCI; SPONDYLITIS, ANKYLOSING;

EID: 84964772502     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng.3528     Document Type: Article

References (55)

1. Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 491, 119-124 (2012).
2. Parkes M, Cortes A, van Heel D.A, & Brown M.A. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14, 661-673 (2013).
3. Najarian D.J, & Gottlieb A.B. Connections between psoriasis and Crohn?s disease. J. Am. Acad. Dermatol. 48, 805-821, quiz 822-824 (2003).
4. Loftus E.V. Jr, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 54, 91-96 (2005).
5. Jensen A.B, et al. Temporal disease trajectories condensed from population-wide registry data covering 6.2 million patients. Nat. Commun. 5, 4022 (2014).
6. Bhattacharjee S, et al. A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits. Am. J. Hum. Genet. 90, 821-835 (2012).
7. Stahl E.A, et al. Genome-wide association study meta-Analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508-514 (2010).
8. Grant S.F, et al. Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes. Diabetes. 58, 290-295 (2009).
9. Wang Z, et al. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33. Hum. Mol. Genet. 23, 6616-6633 (2014).
10. Hindorff L.A, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA. 106, 9362-9367 (2009).
11. Fehrmann R.S, et al. Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet. 7, e1002197 (2011).
12. Nelis M, et al. Genetic structure of Europeans: a view from the North-East. PLoS One 4, e5472 (2009).
13. Trynka G, et al. Disentangling the effects of colocalizing genomic annotations to functionally prioritize non-coding variants within complex-Trait loci. Am. J. Hum. Genet. 97, 139-152 (2015).
14. Roadmap Epigenomics Consortium. Integrative analysis of 111 reference human epigenomes. Nature. 518, 317-330 (2015).
15. FANTOM Consortium and the RIKEN PMI and CLST (DGT). A promoter-level mammalian expression atlas. Nature. 507, 462-470 (2014).
16. Ernst J, et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. 473, 43-49 (2011).
17. Pers T.H, et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat. Commun. 6, 5890 (2015).
18. Fehrmann R.S, et al. Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat. Genet. 47, 115-125 (2015).
19. Kamburov A, et al. ConsensusPathDB: toward a more complete picture of cell biology. Nucleic Acids Res. 39, D712-D717 (2011).
20. Han B, et al. Using genotype data to distinguish pleiotropy from heterogeneity: deciphering coheritability in autoimmune and neuropsychiatric diseases. bioRxiv doi:10.1101/030783 (6 November 2015).
21. Lee S.H, Wray N.R, Goddard M.E, & Visscher P.M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294-305 (2011).
22. Lee S.H, Yang J, Goddard M.E, Visscher P.M, & Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. Bioinformatics. 28, 2540-2542 (2012).
23. Chen G.B, et al. Estimation and partitioning of (co)heritability of inflammatory bowel disease from GWAS and immunochip data. Hum. Mol. Genet. 23, 4710-4720 (2014).
24. Grant A.J, Lalor P.F, Salmi M, Jalkanen S, & Adams D.H. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet. 359, 150-157 (2002).
25. Adams D.H, & Eksteen B. Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease. Nat. Rev. Immunol. 6, 244-251 (2006).
26. Apetoh L, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050-1059 (2007).
27. Prohinar P, Rallabhandi P, Weiss J.P, & Gioannini T.L. Expression of functional D299G.T399I polymorphic variant of TLR4 depends more on coexpression of MD-2 than does wild-Type TLR4. J. Immunol. 184, 4362-4367 (2010).
28. Isakov N, & Altman A. PKC?-mediated signal delivery from the TCR/CD28 surface receptors. Front. Immunol. 3, 273 (2012).
29. Wachowicz K, & Baier G. Protein kinase C?: the pleiotropic T-cell signalling intermediate. Biochem. Soc. Trans. 42, 1512-1518 (2014).
30. Zanin-Zhorov A, et al. Protein kinase C? mediates negative feedback on regulatory T cell function. Science. 328, 372-376 (2010).
31. Anderson C.A, et al. Meta-Analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43, 246-252 (2011).
32. Solovieff N, Cotsapas C, Lee P.H, Purcell S.M, & Smoller J.W. Pleiotropy in complex traits: challenges and strategies. Nat. Rev. Genet. 14, 483-495 (2013).
33. Karlsen T.H, & Boberg K.M. Update on primary sclerosing cholangitis. J. Hepatol. 59, 571-582 (2013).
34. de Vries A.B, Janse M, Blokzijl H, & Weersma R.K. Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis. World J. Gastroenterol. 21, 1956-1971 (2015).
35. Fairfax B.P, et al. Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat. Genet. 44, 502-510 (2012).
36. International Genetics of Ankylosing Spondylitis Consortium (IGAS). Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat. Genet. 45, 730-738 (2013).
37. Tsoi L.C, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat. Genet. 44, 1341-1348 (2012).
38. Liu J.Z, et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat. Genet. 45, 670-675 (2013).
39. Goyette P, et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1 01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat. Genet. 47, 172-179 (2015).
40. Trynka G, et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43, 1193-1201 (2011).
41. 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature. 491, 56-65 (2012).
42. Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559-575 (2007).
43. Price A.L, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904-909 (2006).
44. International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature. 449, 851-861 (2007).
45. Price A.L, et al. Long-range LD can confound genome scans in admixed populations. Am. J. Hum. Genet. 83, 132-135, author reply 135-139 (2008).
46. Abraham G, & Inouye M. Fast principal component analysis of large-scale genome-wide data. PLoS One 9, e93766 (2014).
47. Taylor J.E, Worsley K.J, & Gosselin F. Maxima of discretely sampled random fields, with an application to ?bubbles?. Biometrika. 94, 1-18 (2007).
48. Tsoi L.C, et al. Enhanced meta-Analysis and replication studies identify five new psoriasis susceptibility loci. Nat. Commun. 6, 7001 (2015).
49. Liu J.Z, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979-986 (2015).
50. Morris J.A, Randall J.C, Maller J.B, & Barrett J.C. Evoker: a visualization tool for genotype intensity data. Bioinformatics. 26, 1786-1787 (2010).
51. McLaren W, et al. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics. 26, 2069-2070 (2010).
52. Ng P.C, & Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 31, 3812-3814 (2003).
53. Adzhubei I.A, et al. A method and server for predicting damaging missense mutations. Nat. Methods. 7, 248-249 (2010).
54. 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).
55. Chang C.C, et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 4, 7 (2015).