Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease
Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease
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DOI：
10.1038/ng.733
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发表时间：
2011-01-01
期刊：
影响因子：
30.8
通讯作者：
Georges, Michel
中科院分区：
文献类型：
--
作者：
Momozawa, Yukihide;Mni, Myriam;Georges, Michel
全基因组关联研究（GWAS）已经确定了许多复杂疾病的数十个风险位点，包括克罗恩病（1，2）。然而，常见疾病相关的SNP最多只能解释克罗恩病20%的遗传变异。几个因素可能解释了这种无法解释的遗传性（3-5），包括迄今为止在GWAS中没有充分标记的罕见风险变异（6-8）。罕见的易感性变体确实有助于多因素表型的变化，已被证明是结直肠癌（9）、血浆高密度脂蛋白胆固醇水平（10）、血压（11）、1型糖尿病（12）、高脂蛋白血症（13）以及克罗恩病的NOD 2（参考文献11）。14、15）。在这里，我们描述了使用高通量重测序的DNA池，以寻找罕见的编码变异影响克罗恩病的易感性在63 GWAS确定的位置候选基因。我们确定了低频率的编码变异，赋予保护免受炎症性肠病的IL 23 R，但我们的结论是，罕见的编码变异的位置候选人不作出很大的贡献，遗传易感性克罗恩病。
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.