阿片类药物依赖的全外显子组测序研究为了解外显子组变异的贡献提供了新的视角

Lu Wang, Yaira Z. Nunez, Henry Kranzler, Hang Zhou, Joel Gelernter
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摘要

阿片类药物依赖(OD)在美国流行,并与多种不良健康影响相关。据估计,其遗传率约为 50%,最近的全基因组关联研究已经发现了十几种常见的风险变异。然而,目前还没有关于罕见 OD 风险变异的公开研究。在这项研究中,我们分析了来自耶鲁-宾夕法尼亚大学队列的全外显子组测序数据,其中包括 2100 名欧洲血统(EUR;1321 个 OD 病例)和 1790 名非洲血统(AFR;864 个病例)的参与者。在欧洲人中发现了 RUVBL2 基因中的一个新型低频变异体(rs746301110)(p=6.59*10-10)。在欧洲人中的TMCO3、非洲人中的NEIL2和CFAP44以及跨种系荟萃分析中的FAM210B中都观察到了提示性关联(p<1*10-5)。基于基因的折叠测试发现,SLC22A10、TMCO3、FAM90A1、DHX58、CHRND、GLDN、PLAT、H1-4、COL3A1、GPHB5和QPCTL是最重要的基因(p<1*10-4),其中大多数关联归因于罕见变异,并由预测的功能缺失和错义变异所驱动。这项研究开始填补我们对 OD 遗传结构认识上的空白,为罕见编码变异的贡献以及未来功能研究和药物开发的潜在靶点提供了见解。
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Whole-exome sequencing study of opioid dependence offers novel insights into the contributions of exome variants
Opioid dependence (OD) is epidemic in the United States and it is associated with a variety of adverse health effects. Its estimated heritability is ~50%, and recent genome-wide association studies have identified more than a dozen common risk variants. However, there are no published studies of rare OD risk variants. In this study, we analyzed whole-exome sequencing data from the Yale-Penn cohort, comprising 2,100 participants of European ancestry (EUR; 1,321 OD cases) and 1,790 of African ancestry (AFR; 864 cases). A novel low-frequency variant (rs746301110) in the RUVBL2 gene was identified in EUR (p=6.59*10-10). Suggestive associations (p<1*10-5) were observed in TMCO3 in EUR, in NEIL2 and CFAP44 in AFR, and in FAM210B in the cross-ancestry meta-analysis. Gene-based collapsing tests identified SLC22A10, TMCO3, FAM90A1, DHX58, CHRND, GLDN, PLAT, H1-4, COL3A1, GPHB5 and QPCTL as top genes (p<1*10-4) with most associations attributable to rare variants and driven by the burden of predicted loss-of-function and missense variants. This study begins to fill the gap in our understanding of the genetic architecture of OD, providing insights into the contribution of rare coding variants and potential targets for future functional studies and drug development.
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