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

被引：608

作者：

Ellinghaus, David ^{[1
,50
]}

Jostins, Luke ^{[2
]}

Spain, Sarah L. ^{[2
]}

Cortes, Adrian ^{[3
,4
]}

Bethune, Joern ^{[1
]}

Han, Buhm ^{[5
,6
]}

Park, Yu Rang ^{[7
]}

Raychaudhuri, Soumya ^{[8
,9
,10
,11
]}

Pouget, Jennie G. ^{[12
,13
]}

Huebenthal, Matthias ^{[1
]}

Folseraas, Trine ^{[14
,15
,16
,17
]}

Wang, Yunpeng ^{[18
]}

Esko, Tonu ^{[19
,20
,21
]}

Metspalu, Andres ^{[19
]}

Westra, Harm-Jan ^{[8
,9
,10
,11
]}

Franke, Lude ^{[22
]}

Pers, Tune H. ^{[8
,21
,23
,24
]}

Weersma, Rinse K. ^{[25
]}

Collij, Valerie ^{[25
]}

D'Amato, Mauro ^{[26
,27
,28
]}

Halfvarson, Jonas ^{[29
]}

Jensen, Anders Boeck ^{[30
]}

Lieb, Wolfgang ^{[31
,32
]}

Degenhardt, Franziska ^{[33
,34
]}

Forstner, Andreas J. ^{[33
,34
]}

Hofmann, Andrea ^{[33
,34
]}

Schreiber, Stefan ^{[1
,35
]}

Mrowietz, Ulrich ^{[36
]}

Juran, Brian D. ^{[37
]}

Lazaridis, Konstantinos N. ^{[37
]}

Brunak, Soren ^{[30
]}

Dale, Anders M. ^{[18
,38
]}

Trembath, Richard C. ^{[39
]}

Weidinger, Stephan ^{[36
]}

Weichenthal, Michael ^{[36
]}

Ellinghaus, Eva ^{[1
]}

Elder, James T. ^{[40
,41
]}

Barker, Jonathan N. W. N. ^{[42
]}

Andreassen, Ole A. ^{[43
,44
]}

McGovern, Dermot P. ^{[45
,46
]}

Karlsen, Tom H. ^{[14
,15
,16
,17
]}

Barrett, Jeffrey C. ^{[2
]}

Parkes, Miles ^{[47
]}

Brown, Matthew A. ^{[48
,49
]}

Franke, Andre ^{[1
]}

机构：

[1] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[2] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England

[3] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Div Clin Neurol, Oxford OX3 9DU, England

[4] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[5] Univ Ulsan, Coll Med, Dept Convergence Med, Seoul, South Korea

[6] Asan Med Ctr, Asan Inst Life Sci, Seoul, South Korea

[7] Univ Ulsan, Asan Inst Life Sci, Asan Med Ctr, Coll Med, Seoul, South Korea

[8] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[9] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA

[10] Brigham & Womens Hosp, Div Rheumatol, 75 Francis St, Boston, MA 02115 USA

[11] Harvard Sch Med, Dept Med, Boston, MA USA

[12] Campbell Family Mental Hlth Res Inst, Ctr Addict & Mental Hlth, Toronto, ON, Canada

[13] Univ Toronto, Dept Psychiat, Toronto, ON, Canada

[14] Oslo Univ Hosp, Norwegian PSC Res Ctr, Div Canc Med Surg & Transplantat, Dept Transplantat Med,Rikshosp, N-0450 Oslo, Norway

[15] Univ Oslo, KG Jebsen Inflammat Res Ctr, Inst Clin Med, Oslo, Norway

[16] Oslo Univ Hosp, Res Inst Internal Med, Div Canc Med Surg & Transplantat, Rikshosp, Oslo, Norway

[17] Oslo Univ Hosp, Dept Transplantat Med, Gastroenterol Sect, N-0450 Oslo, Norway

[18] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA

[19] Univ Tartu, Estonian Genome Ctr, Ulikooli 18, EE-50090 Tartu, Estonia

[20] Boston Childrens Hosp, Div Endocrinol, Cambridge, MA USA

[21] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Cambridge, MA USA

[22] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[23] Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark

[24] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark

[25] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands

[26] Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden

[27] BioCruces Hlth Res Inst, Bilbao, Spain

[28] Ikerbasque, Basque Fdn Sci, E-48011 Bilbao, Spain

[29] Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, SE-70182 Orebro, Sweden

[30] Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, Copenhagen, Denmark

[31] Univ Hosp Schleswig Holstein, Inst Epidemiol, Kiel, Germany

[32] Univ Hosp Schleswig Holstein, PopGen Biobank, Kiel, Germany

[33] Univ Bonn, Inst Human Genet, Bonn, Germany

[34] Univ Bonn, Dept Genom Life & Brain Ctr, Bonn, Germany

[35] Univ Klinikum Schleswig Holstein, Dept Gen Internal Med, Campus Kiel, Kiel, Germany

[36] Univ Kiel, Dept Dermatol, Univ Hosp, Schleswig Holstein, Schittenhelmstr 7, Kiel, Germany

[37] Mayo Clin, Ctr Basic Res Digest Dis, Div Gastroenterol & Hepatol, Coll Med, Rochester, MN USA

[38] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA

[39] Kings Coll London, Div Genet & Mol Med, London, England

[40] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA

[41] Ann Arbor Vet Affairs Hosp, Ann Arbor, MI USA

[42] Kings Coll London, St Johns Inst Dermatol, Div Genet & Mol Med, London, England

[43] Univ Oslo, NORMENT, KG Jebsen Ctr Psychosis Res, Inst Clin Med, Oslo, Norway

[44] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[45] F Widjaja Fdn Inflammatory Bowel & Immunobiol Res, Los Angeles, CA USA

[46] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[47] Univ Cambridge, Addenbrookes Hosp, Inflammatory Bowel Dis Res Grp, Cambridge CB2 2QQ, England

[48] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia

[49] Queensland Univ Technol, IHBI, Translat Res Inst, Brisbane, Qld 4001, Australia

[50] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

来源：

NATURE GENETICS | 2016年 / 48卷 / 05期

基金：

瑞典研究理事会; 欧盟地平线“2020”;

关键词：

GENOME-WIDE ASSOCIATION; KINASE C-THETA; BOWEL-DISEASE; RISK LOCI; SUSCEPTIBILITY LOCI; GENE-EXPRESSION; METAANALYSIS; VARIANTS; COMMON; PLEIOTROPY;

D O I：

10.1038/ng.3528

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

引用

页码：510 / +

页数：12

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