Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

被引：590

作者：

Rivas, Manuel A. ^{[1
,2
,3
]}

Beaudoin, Melissa ^{[4
,5
]}

Gardet, Agnes ^{[6
,7
]}

Stevens, Christine ^{[2
]}

Sharma, Yashoda ^{[8
]}

Zhang, Clarence K. ^{[8
]}

Boucher, Gabrielle ^{[4
,5
]}

Ripke, Stephan ^{[1
,2
]}

Ellinghaus, David ^{[9
]}

Burtt, Noel ^{[2
]}

Fennell, Tim ^{[2
]}

Kirby, Andrew ^{[1
,2
]}

Latiano, Anna ^{[10
]}

Goyette, Philippe ^{[4
,5
]}

Green, Todd ^{[2
]}

Halfvarson, Jonas ^{[11
,12
]}

Haritunians, Talin ^{[13
]}

Korn, Joshua M. ^{[2
]}

Kuruvilla, Finny ^{[2
,14
]}

Lagace, Caroline ^{[4
,5
]}

Neale, Benjamin ^{[1
,2
]}

Lo, Ken Sin ^{[4
,5
]}

Schumm, Phil ^{[15
]}

Torkvist, Leif ^{[16
]}

Dubinsky, Marla C. ^{[17
]}

Brant, Steven R. ^{[18
,19
]}

Silverberg, Mark S. ^{[20
]}

Duerr, Richard H. ^{[21
,22
]}

Altshuler, David ^{[1
,2
]}

Gabriel, Stacey ^{[2
]}

Lettre, Guillaume ^{[4
,5
]}

Franke, Andre ^{[9
]}

D'Amato, Mauro ^{[23
]}

McGovern, Dermot P. B. ^{[13
,24
]}

Cho, Judy H. ^{[8
]}

Rioux, John D. ^{[4
,5
]}

Xavier, Ramnik J. ^{[1
,2
,6
,7
]}

Daly, Mark J. ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Broad Inst Harvard & MIT, Cambridge, MA USA

[3] Univ Oxford, Nuffield Dept Clin Med, Oxford, England

[4] Univ Montreal, Montreal, PQ, Canada

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

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

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

[8] Yale Univ, Sch Med, New Haven, CT USA

[9] Inst Clin Mol Biol, Kiel, Germany

[10] Casa Sollievo Sofferenza Hosp, Ist Ricovero & Cura Carattere Sci, Gastroenterol Unit, San Giovanni Rotondo, Italy

[11] Univ Orebro, Dept Med, Orebro Univ Hosp, Orebro, Sweden

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

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

[14] Clarus Ventures, Cambridge, MA USA

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

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

[17] Cedars Sinai Med Ctr, Pediat Inflammatory Bowel Dis Ctr, Los Angeles, CA 90048 USA

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

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

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

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

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

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

[24] Cedars Sinai Med Ctr, Inflammatory Bowel & Immunobiol Res Inst, Los Angeles, CA 90048 USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 11期

基金：

加拿大健康研究院; 瑞典研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CROHN-DISEASE; CARD15; MUTATIONS; NOD2; FREQUENCY; RISK; RECRUITMENT; AUTOPHAGY; SELECTION;

D O I：

10.1038/ng.952

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 x 10(-16), odds ratio approximate to 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

引用

页码：1066 / U50

页数：10

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