Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci
Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci
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DOI：
10.1073/pnas.0706645104
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发表时间：
2007-09-11
影响因子：
11.1
通讯作者：
Schreiber, Stefan
中科院分区：
文献类型：
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作者：
Raelson, John V.;Little, Randall D.;Schreiber, Stefan
全基因组关联（GWA）研究为复杂疾病的多个易感基因的鉴定提供了一种强有力的无偏方法。在这里，我们报告的结果，GWA研究克罗恩病（CD）使用家庭三人组从魁北克方正人口（QFP）。基于单倍型的关联分析确定了与疾病相关的多个区域，这些区域符合全基因组意义的标准，其中许多区域含有功能似乎与CID相关的基因。其中一部分在两个独立的德国高加索人样本中得到了重复，包括已建立的CD位点NOD2和IBD 5。最近描述的IL23R基因座也被鉴定和复制。对于该区域，对QFP中具有所有主要单倍型的多个个体进行测序，并进行广泛的精细作图以鉴定风险和保护性等位基因。几个额外的基因座，包括3p21上含有几个可能的候选基因的区域，4p16.1上靠近JAKMIP 1的区域，以及17号染色体上两个较大的区域被复制。连同先前发表的基因座，迄今为止鉴定的CD基因谱涉及影响上皮防御机制、先天性和适应性免疫应答以及组织修复或重塑的生化网络。
Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CID. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.