Identification of genetic risk variants for inflammatory bowel disease (IBD)

大多数复杂的疾病部分根源于基因组。炎症性肠病（IBD）是一种复杂的疾病，包括结肠和小肠的慢性炎症。IBD的两种主要类型是克罗恩病和溃疡性结肠炎。IBD的病因尚不清楚，但遗传易感性占疾病病例的50%。连锁和全基因组关联研究（GWAS）已将许多遗传区域与IBD相关联。然而，这些协会是弱的，不能解释观察到的遗传性。此外，由于这些研究的分辨率较低，因此仍然很难确定哪些变体在机制上负责相关性。因此，已知的IBD风险基因座不足以预测疾病或解释疾病病因。我建议应用全基因组测序来识别新的IBD风险变体。我将分析IBD发病率高的家庭，这就是为什么这项研究有能力确定具有强烈影响和中度至高度致病性的致病性遗传变异。我将通过流行病学和实验验证候选风险变量。流行病学验证，我将确定候选人窝藏单倍型，并确定单核苷酸多态性（SNP）的单倍型特异性模式。使用这些SNP模式，我将推断现有GWAS数据集中的候选变体，并测试IBD的分离。为了进行功能验证，我将使用来自测序家族的血液样本，并分析受我的候选变体影响的基因的转录水平。此外，我将通过实验评估候选人的功能，并测试它们是否影响免疫调节或屏障功能。我的初步结果表明，这项研究可以揭示新的IBD风险变异，这将有助于解释遗传性和了解IBD病因。

Most complex diseases are partly rooted in the genome. Inflammatory bowel disease (IBD) is a complex disorder encompassing chronic inflammatory conditions of the colon and the small intestine. The two major types of IBD are Crohn's disease and ulcerative colitis. The cause of IBD remains unknown but genetic predisposition accounts for up to 50% of disease cases. Linkage and genome-wide association studies (GWAS) have associated many genetic regions with IBD. However, these associations are weak and fall short in explaining the observed heritability. Furthermore, it remains mostly elusive which variants are mechanistically responsible for the associations because of the low resolution of these studies. As a result the known IBD risk loci are insufficient to predict disease or explain disease etiology. I propose to apply whole-genome sequencing to identify new IBD risk variants. I will analyze families with a high incidence of IBD, which is why this study has the power to identify causative genetic variants that have strong effects and moderate to high penetrance. I will validate the candidate risk variants epidemiologically and experimentally. For epidemiologic validation I will identify the candidate harboring haplotypes and determine the haplotype-specific patterns of single nucleotide polymorphisms (SNPs). Using these SNP patterns I will infer the candidate variants in existing GWAS data sets and test for segregation with IBD. For functional validation I will use blood samples from the sequenced families and analyze transcript levels of the genes affected by my candidate variants. Moreover, I will experimentally assess the function of the candidates and I will test if they affect immune regulation or barrier function. My preliminary results indicate that this study can reveal new IBD risk variants, which will help to explain heritability and understand IBD etiology.