Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19194, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19194, USA.
Am J Hum Genet. 2021 Mar 4;108(3):482-501. doi: 10.1016/j.ajhg.2021.02.008. Epub 2021 Feb 25.
Rare monogenic disorders of the primary cilium, termed ciliopathies, are characterized by extreme presentations of otherwise common diseases, such as diabetes, hepatic fibrosis, and kidney failure. However, despite a recent revolution in our understanding of the cilium's role in rare disease pathogenesis, the organelle's contribution to common disease remains largely unknown. Hypothesizing that common genetic variants within Mendelian ciliopathy genes might contribute to common complex diseases pathogenesis, we performed association studies of 16,874 common genetic variants across 122 ciliary genes with 12 quantitative laboratory traits characteristic of ciliopathy syndromes in 452,593 individuals in the UK Biobank. We incorporated tissue-specific gene expression analysis, expression quantitative trait loci, and Mendelian disease phenotype information into our analysis and replicated our findings in meta-analysis. 101 statistically significant associations were identified across 42 of the 122 examined ciliary genes (including eight novel replicating associations). These ciliary genes were widely expressed in tissues relevant to the phenotypes being studied, and eQTL analysis revealed strong evidence for correlation between ciliary gene expression levels and laboratory traits. Perhaps most interestingly, our analysis identified different ciliary subcompartments as being specifically associated with distinct sets of phenotypes. Taken together, our data demonstrate the utility of a Mendelian pathway-based approach to genomic association studies, challenge the widely held belief that the cilium is an organelle important mainly in development and in rare syndromic disease pathogenesis, and provide a framework for the continued integration of common and rare disease genetics to provide insight into the pathophysiology of human diseases of immense public health burden.
原发性纤毛罕见的单基因疾病，称为纤毛病，其特征是通常常见疾病的极端表现，如糖尿病、肝纤维化和肾衰竭。然而，尽管我们最近对纤毛在罕见疾病发病机制中的作用有了新的认识，但该细胞器对常见疾病的贡献在很大程度上仍不清楚。我们假设孟德尔纤毛病基因中的常见遗传变异可能会导致常见的复杂疾病发病机制，因此我们对 122 个纤毛基因中的 16874 个常见遗传变异与英国生物库中 452593 名个体的 12 个与纤毛病综合征特征相关的定量实验室特征进行了关联研究。我们将组织特异性基因表达分析、数量性状基因座和孟德尔疾病表型信息纳入我们的分析中，并在荟萃分析中复制了我们的发现。在 122 个被检查的纤毛基因中的 42 个基因中发现了 101 个具有统计学意义的关联（包括 8 个新的重复关联）。这些纤毛基因在与研究表型相关的组织中广泛表达，eQTL 分析显示纤毛基因表达水平与实验室特征之间存在很强的相关性。也许最有趣的是，我们的分析确定了不同的纤毛亚区与不同的表型集具有特异性关联。总之，我们的数据证明了基于孟德尔途径的基因组关联研究方法的实用性，挑战了纤毛是一个主要在发育和罕见综合征发病机制中重要的细胞器的普遍观点，并为罕见和常见疾病遗传学的持续整合提供了框架，以深入了解对公众健康负担巨大的人类疾病的病理生理学。
