Rare-variant pathogenicity triage and inclusion of synonymous variants improves analysis of disease associations of orphan G protein?coupled receptors
Rare-variant pathogenicity triage and inclusion of synonymous variants improves analysis of disease associations of orphan G protein?coupled receptors
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DOI：
10.1074/jbc.ra119.009253
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发表时间：
2019-11-29
影响因子：
4.8
通讯作者：
Mitnaul, L. J.
中科院分区：
文献类型：
--
作者：
Dershem, Ridge;Metpally, Raghu P. R.;Mitnaul, L. J.
G蛋白脱乙酰化的步伐？偶联受体（GPCR）的研究已经放缓，需要新的方法。孤儿GPCR的小分子靶向可能具有临床益处，即使尚未鉴定内源性受体配体。许多GPCR缺乏导致可再现的全基因组疾病关联的常见变体，并且罕见变体方法已成为鉴定此类基因的疾病关联的可行替代方案。因此，我们的目标是通过在大量临床人群中确定孤儿GPCR与人类疾病的相关性来优先考虑孤儿GPCR。我们使用序列核关联检验来评估一个包含51，289名个体的队列中85个孤儿或研究不足的GPCR的疾病关联。使用罕见的功能丧失变体，预测为致病性或可能致病性的错义变体，以及导致局部密码子偏倚发生较大变化的罕见同义变体子集作为独立数据集，我们发现39%的GPCR的两个或更多个变体类别共享强大的表型疾病关联。为了验证生物信息学和序列核关联检验分析，我们在功能上表征了GPR39的罕见错义和同义变体，这是一个家族A GPCR，揭示了两个变体类别成员的表达或Zn 2+介导的信号传导的改变。这些结果支持罕见变异分析用于鉴定缺乏有影响力的常见变异的GPCR的疾病关联的效用。我们强调了罕见的同义变异在人类生理学中的重要性，并主张将其常规纳入任何全面的基因组变异分析中，作为疾病的潜在原因。
The pace of deorphanization of G protein?coupled receptors (GPCRs) has slowed, and new approaches are required. Small molecule targeting of orphan GPCRs can potentially be of clinical benefit even if the endogenous receptor ligand has not been identified. Many GPCRs lack common variants that lead to reproducible genome-wide disease associations, and rare-variant approaches have emerged as a viable alternative to identify disease associations for such genes. Therefore, our goal was to prioritize orphan GPCRs by determining their associations with human diseases in a large clinical population. We used sequence kernel association tests to assess the disease associations of 85 orphan or understudied GPCRs in an unselected cohort of 51,289 individuals. Using rare loss-of-function variants, missense variants predicted to be pathogenic or likely pathogenic, and a subset of rare synonymous variants that cause large changes in local codon bias as independent data sets, we found strong, phenome-wide disease associations shared by two or more variant categories for 39% of the GPCRs. To validate the bioinformatics and sequence kernel association test analyses, we functionally characterized rare missense and synonymous variants of GPR39, a family A GPCR, revealing altered expression or Zn2+-mediated signaling for members of both variant classes. These results support the utility of rare variant analyses for identifying disease associations for GPCRs that lack impactful common variants. We highlight the importance of rare synonymous variants in human physiology and argue for their routine inclusion in any comprehensive analysis of genomic variants as potential causes of disease.