Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.
Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.
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DOI：
10.1371/journal.pgen.1003723
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Rioux JD
中科院分区：
文献类型：
--
作者：
Beaudoin M;Goyette P;Boucher G;Lo KS;Rivas MA;Stevens C;Alikashani A;Ladouceur M;Ellinghaus D;Törkvist L;Goel G;Lagacé C;Annese V;Bitton A;Begun J;Brant SR;Bresso F;Cho JH;Duerr RH;Halfvarson J;McGovern DP;Radford-Smith G;Schreiber S;Schumm PL;Sharma Y;Silverberg MS;Weersma RK;Quebec IBD Genetics Consortium;NIDDK IBD Genetics Consortium;International IBD Genetics Consortium;D'Amato M;Vermeire S;Franke A;Lettre G;Xavier RJ;Daly MJ;Rioux JD
克罗恩病（CD）和溃疡性结肠炎（UC）的全基因组关联研究和随访荟萃分析最近确定了163个疾病相关基因座，这些基因座符合这两种炎症性肠病（IBD）的全基因组意义。这些发现已经对我们理解这些疾病的遗传结构产生了巨大的影响，并指导了功能研究，揭示了一些对IBD重要的生物学功能（例如自噬）。尽管如此，这些基因座只能解释一小部分疾病变异（CD中约14%，UC中约7.5%），这表明不仅可以发现其他基因座，而且已知基因座可能包含GWAS未检测到的高效应罕见风险变异。为了验证这一点，我们在200例UC病例和150例健康对照（HC）（均为法裔加拿大人）中使用了靶向测序方法，以研究与UC相关区域的55个基因。我们在独立的病例对照队列中对42种罕见的非同义变异进行了随访基因分型（共14，435例UC病例和20，204例HC）。我们的结果证实了与IL 23 R和CARD 9中罕见的非同义编码变体的显著关联，这些变体先前从CD基因座的测序中鉴定，并且鉴定了RNF 186中的新关联。除了CARD 9（OR = 0.39）之外，鉴定的罕见非同义变体具有中等效果（对于RNF 186，OR=1.49，对于IL 23 R，OR=0.79）。 RNF 186编码具有RING结构域和两个跨膜结构域的蛋白质，所述RING结构域具有预测的E3泛素-蛋白质连接酶活性。重要的是，疾病编码变体位于泛素连接酶结构域中。最后，我们的研究结果表明，在UC中通过全基因组关联鉴定的基因中的罕见变异不太可能对疾病的总体方差有显著贡献。相反，这些有望有助于集中相应疾病位点的功能研究。在过去的五年中，常见疾病的遗传学研究取得了巨大进展，主要是由于最近的技术能够系统地检查大量患者和健康对照的整个基因组的遗传标记。这些研究虽然确定了影响一个人患病风险的基因组区域，但往往没有确定导致这种风险的实际基因或基因变异（称为因果基因/变异）。这方面的一个主要例子是最近与慢性炎症性肠病（称为克罗恩病和溃疡性结肠炎）相关的163种遗传风险因素。因为在这163个基因中，只有不到一小部分是已知遗传密码中的致病变化。目前的研究使用了一种方法来直接观察其中一个子集的遗传密码，并确定了溃疡性结肠炎8个风险因素的遗传密码的致病变化。这一发现特别重要，因为它指导了生物学研究，以了解导致这种慢性终身炎症性疾病的机制。
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 (∼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. Genetic studies of common diseases have seen tremendous progress in the last half-decade primarily due to recent technologies that enable a systematic examination of genetic markers across the entire genome in large numbers of patients and healthy controls. The studies, while identifying genomic regions that influence a person's risk for developing disease, often do not pinpoint the actual gene or gene variants that account for this risk (called a causal gene/variant). A prime example of this can be seen with the 163 genetic risk factors that have recently been associated with the chronic inflammatory bowel diseases known as Crohn's disease and ulcerative colitis. For less than a handful of these 163 is the causative change in the genetic code known. The current study used an approach to directly look at the genetic code for a subset of these and identified a causative change in the genetic code for eight risk factors for ulcerative colitis. This finding is particularly important because it directs biological studies to understand the mechanisms that lead to this chronic life-long inflammatory disease.
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