Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

被引：155

作者：

Beaudoin, Melissa ^{[1
]}

Goyette, Philippe ^{[1
]}

Boucher, Gabrielle ^{[1
]}

Lo, Ken Sin ^{[1
]}

Rivas, Manuel A. ^{[2
]}

Stevens, Christine ^{[2
]}

Alikashani, Azadeh ^{[1
]}

Ladouceur, Martin ^{[1
]}

Ellinghaus, David ^{[3
]}

Torkvist, Leif ^{[4
]}

Goel, Gautam ^{[5
,6
]}

Lagace, Caroline ^{[1
]}

Annese, Vito ^{[7
,8
]}

Bitton, Alain ^{[9
]}

Begun, Jakob ^{[5
,6
]}

Brant, Steve R. ^{[10
,11
]}

Bresso, Francesca ^{[12
]}

Cho, Judy H. ^{[13
,14
]}

Duerr, Richard H. ^{[15
,16
]}

Halfvarson, Jonas ^{[17
,18
]}

McGovern, Dermot P. B. ^{[19
,20
]}

Radford-Smith, Graham ^{[21
,22
,23
]}

Schreiber, Stefan ^{[3
,24
]}

Schumm, Philip L. ^{[25
]}

Sharma, Yashoda ^{[13
,14
]}

Silverberg, Mark S. ^{[26
]}

Weersma, Rinse K. ^{[27
,28
]}

D'Amato, Mauro ^{[29
]}

Vermeire, Severine ^{[30
]}

Franke, Andre ^{[24
]}

Lettre, Guillaume ^{[1
,31
]}

Xavier, Ramnik J. ^{[5
,6
,32
]}

Daly, Mark J. ^{[33
]}

Rioux, John D. ^{[1
,31
]}

机构：

[1] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada

[2] Broad Inst, Ctr Study IBD CSIBD Genet, Cambridge, MA USA

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

[4] Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden

[5] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA

[6] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA

[7] Ist Ricovero & Cura Carattere Sci Casa Sollievo S, Gastroenterol Unit, San Giovanni Rotondo, Italy

[8] Azienda Osped Univ AOU Careggi, Unit Gastroenterol SOD2, Florence, Italy

[9] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Div Gastroenterol, Montreal, PQ H3A 1A1, Canada

[10] Johns Hopkins Univ, Sch Med, Dept Med, Meyerhoff Inflammatory Bowel Dis Ctr, Baltimore, MD 21205 USA

[11] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[12] Karolinska Univ Hosp, Dept Med, Solna, Sweden

[13] Yale Univ, Dept Med, New Haven, CT 06520 USA

[14] Yale Univ, Dept Genet, New Haven, CT USA

[15] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA

[16] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[17] Orebro Univ Hosp, Dept Internal Med, Div Gastroenterol, Orebro, Sweden

[18] Univ Orebro, Sch Hlth & Med Sci, Orebro, Sweden

[19] Cedars Sinai Med Ctr, Cedars Sinai F Widjaja Inflammatory Bowel & Immun, Los Angeles, CA 90048 USA

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

[21] Univ Queensland, Royal Brisbane & Womens Hosp, Queensland Inst Med Res, Brisbane, Qld, Australia

[22] Univ Queensland, Royal Brisbane & Womens Hosp, Dept Gastroenterol, Brisbane, Qld, Australia

[23] Univ Queensland, Sch Med, Brisbane, Qld, Australia

[24] Univ Kiel, Dept Gen Internal Med, Kiel, Germany

[25] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA

[26] Univ Toronto, Mt Sinai Hosp, Ctr Inflammatory Bowel Dis, Toronto, ON M5G 1X5, Canada

[27] Univ Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands

[28] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands

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

[30] Univ Hosp Gasthuisberg, Div Gastroenterol, B-3000 Louvain, Belgium

[31] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada

[32] Broad Inst MIT & Harvard Univ, Cambridge, MA USA

[33] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit, Boston, MA USA

来源：

PLOS GENETICS | 2013年 / 9卷 / 09期

基金：

加拿大健康研究院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; NUCLEAR FACTOR 4-ALPHA; SUSCEPTIBILITY LOCI; UBIQUITIN LIGASES; GENETIC-VARIANTS; CROHN-DISEASE; EXPRESSION; MODULATION; CELLS;

D O I：

10.1371/journal.pgen.1003723

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (similar to 14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

引用

页数：11

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