Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease

被引：166

作者：

Momozawa, Yukihide ^{[1
,2
]}

Mni, Myriam ^{[1
,2
]}

Nakamura, Kayo ^{[1
,2
]}

Coppieters, Wouter ^{[1
,2
]}

Almer, Sven ^{[3
]}

Amininejad, Leila ^{[4
]}

Cleynen, Isabelle ^{[5
]}

Colombel, Jean-Frederic ^{[6
]}

de Rijk, Peter ^{[7
]}

Dewit, Olivier ^{[8
]}

Finkel, Yigael ^{[9
]}

Gassull, Miquel A. ^{[10
]}

Goossens, Dirk ^{[7
]}

Laukens, Debby ^{[11
]}

Lemann, Marc ^{[12
]}

Libioulle, Cecile ^{[1
,2
]}

O'Morain, Colm ^{[13
]}

Reenaers, Catherine ^{[14
,15
]}

Rutgeerts, Paul ^{[5
]}

Tysk, Curt ^{[16
]}

Zelenika, Diana ^{[17
]}

Lathrop, Mark ^{[17
]}

Del-Favero, Jurgen ^{[7
]}

Hugot, Jean-Pierre ^{[18
]}

de Vos, Martine ^{[11
]}

Franchimont, Denis ^{[4
]}

Vermeire, Severine ^{[5
]}

Louis, Edouard ^{[14
,15
]}

Georges, Michel ^{[1
,2
]}

机构：

[1] Grp Interdisciplinaire Genoprote Appliquee GIGA R, Unit Anim Genom, Liege, Belgium

[2] Univ Liege B34, Fac Vet Med, Liege, Belgium

[3] Linkopings Univ, Inst Mol & Klin Med IMK, Div Gastroenterol & Hepatol, Linkoping, Sweden

[4] Univ Libre Brussels, Erasme Hosp, Dept Gastroenterol, Brussels, Belgium

[5] Catholic Univ Louvain, Dept Pathophysiol, Gastroenterol Sect, B-3000 Louvain, Belgium

[6] Hop Calmette, Registre MICI Nord Quest France EPIMAD, Lille, France

[7] Univ Antwerp VIB, Dept Mol Genet, B-2610 Antwerp, Belgium

[8] Catholic Univ Louvain, Clin Univ St Luc, Dept Gastroenterol, B-1200 Brussels, Belgium

[9] Karolinska Childrens Hosp, Dept Gastroenterol, Stockholm, Sweden

[10] Hosp Badalona Germans Trias & Pujol, Dept Gastroenterol, Badalona, Spain

[11] Univ Ghent, Univ Hosp, Dept Gastroenterol, B-9000 Ghent, Belgium

[12] Univ Paris 07, Hop St Louis, AP HP, Dept Gastroenterol, Paris, France

[13] Adelaide & Meath Hosp, Dublin, Ireland

[14] GIGA R, Unit Hepatogastroenterol, Liege, Belgium

[15] Univ Liege B34, Fac Med, Liege, Belgium

[16] Orebro Med Ctr Hosp, Dept Gastroenterol, S-70185 Orebro, Sweden

[17] Ctr Natl Genotypage, Evry, France

[18] Hop Robert Debre, INSERM, U843, F-75019 Paris, France

来源：

NATURE GENETICS | 2011年 / 43卷 / 01期

关键词：

GENOME-WIDE ASSOCIATION; RARE VARIANTS; COMPLEX DISEASES; CROHNS-DISEASE; SUSCEPTIBILITY; GENES; HERITABILITY; CONTRIBUTE; COMMON; SNPS;

D O I：

10.1038/ng.733

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease(1,2). However, common disease-associated SNPs explain at most similar to 20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability(3-5), including rare risk variants not adequately tagged thus far in GWAS(6-8). That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer(9), plasma high-density lipoprotein cholesterol levels(10), blood pressure(11), type 1 diabetes(12), hypertriglyceridemia(13) and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.

引用

页码：43 / U58

页数：6

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