Genomic architecture of inflammatory bowel disease in five families with multiple affected individuals.
Genomic architecture of inflammatory bowel disease in five families with multiple affected individuals.
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五个患有多个患者的家庭的炎症性肠病的基因组结构。
DOI：
10.1038/hgv.2015.60
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发表时间：
2016
影响因子：
1.5
通讯作者：
Glusman G
中科院分区：
文献类型：
--
作者：
Stittrich AB;Ashworth J;Shi M;Robinson M;Mauldin D;Brunkow ME;Biswas S;Kim JM;Kwon KS;Jung JU;Galas D;Serikawa K;Duerr RH;Guthery SL;Peschon J;Hood L;Roach JC;Glusman G
目前，炎症性肠病（IBD）的最佳临床预测因子是家族史。在全基因组关联研究中，超过163种序列变异与IBD相关，但它们的影响很弱，只能解释观察到的遗传性的一小部分。预计其他变异对IBD的基因组结构有贡献，可能包括效应量大于所鉴定的常见变异的罕见变异。在这里，我们应用了一个家族研究设计，并对来自5个家族的38个个体进行了测序，假设有多个IBD受影响个体的家族含有一个或多个风险变体，这些风险变体（i）在受影响的家族成员中共享，（ii）罕见，（iii）对疾病发展有实质性影响。我们的分析不仅揭示了新的候选风险变异，而且在五个家庭中的四个中，常见的已知风险变异的多基因风险评分也很高。我们在剩余家族中的顶级新变体的功能分析，泛素连接酶TRIM 11中的罕见错义突变，表明它导致B细胞中κ轻链增强子（NF-κB）信号传导的核因子增加。我们的结论是，常见弱效应变异的积累导致了我们分析的大多数但不是所有家族中IBD的高发病率，并且家族研究设计可以识别出赋予IBD风险的新的罕见变异，具有潜在的大效应大小，例如TRIM 11 p.H414Y突变。
Currently, the best clinical predictor for inflammatory bowel disease (IBD) is family history. Over 163 sequence variants have been associated with IBD in genome-wide association studies, but they have weak effects and explain only a fraction of the observed heritability. It is expected that additional variants contribute to the genomic architecture of IBD, possibly including rare variants with effect sizes larger than the identified common variants. Here we applied a family study design and sequenced 38 individuals from five families, under the hypothesis that families with multiple IBD-affected individuals harbor one or more risk variants that (i) are shared among affected family members, (ii) are rare and (iii) have substantial effect on disease development. Our analysis revealed not only novel candidate risk variants but also high polygenic risk scores for common known risk variants in four out of the five families. Functional analysis of our top novel variant in the remaining family, a rare missense mutation in the ubiquitin ligase TRIM11, suggests that it leads to increased nuclear factor of kappa light chain enhancer in B-cells (NF-κB) signaling. We conclude that an accumulation of common weak-effect variants accounts for the high incidence of IBD in most, but not all families we analyzed and that a family study design can identify novel rare variants conferring risk for IBD with potentially large effect size, such as the TRIM11 p.H414Y mutation.