与年龄相关听力损失相关的CRIP3变异的群体遗传学和进化背景

文献信息

中文摘要

背景： 年龄相关听力损失是一种广泛的感觉障碍，影响三分之一的老年人口，然而该疾病的遗传基础仍不完全清楚。在本研究中，我们调查了CRIP3基因中一个非同义变异（rs2242416）的进化背景，该基因在听觉毛细胞中表达，并且先前与听力损失相关。我们首先确认rs2242416在多项全基因组关联研究中显示出与听力损失强烈且一致的关联。值得注意的是，rs2242416还与心脏相关表型风险降低相关，提示潜在的多效性效应。该变异在胎盘哺乳动物中高度保守的氨基酸位点将非极性异亮氨酸替换为极性苏氨酸。通过引起氨基酸改变，该变异被预测会轻微改变CRIP3蛋白的结构。此外，CRIP3位点的群体遗传学揭示，在人类5万多年前走出非洲迁徙后，欧亚人群中rs2242416的衍生苏氨酸等位基因频率增加。然而，自然选择在产生欧亚人群中该等位基因频率增加中的作用仍无定论。总之，这些结果为CRIP3变异提供了表型、进化和分子背景，并突出rs2242416作为功能研究的有前景候选。意义声明：年龄相关听力损失非常普遍，然而导致疾病风险的特定遗传变异仍知之甚少。在这里，我们研究了一个导致CRIP3基因氨基酸改变的变异（rs2242416）。虽然该变异在多项全基因组关联研究（GWAS）中与听力损失相关，但几乎未受到集中关注。通过将GWAS发现与进化和群体遗传学分析相结合，我们为解释该变异提供了更广泛的背景。我们的结果支持rs2242416作为增加人类听力损失风险的候选功能变异。总体而言，本研究展示了将群体遗传学与人类GWAS相结合以优先选择变异进行功能验证的价值。

英文摘要

Age-related hearing loss is a widespread sensory impairment affecting one third of the elderly population, yet the genetic underpinnings of this condition remain incompletely understood. In this study, we investigate the evolutionary context of a non-synonymous variant (rs2242416) in the CRIP3 gene, which is expressed in auditory hair cells, and previously associated with hearing loss. We first confirm that rs2242416 shows strong and consistent association with hearing loss across multiple genome-wide association studies. Notably, rs2242416 is also associated with reduced risk of heart related phenotypes, suggesting potential pleiotropic effects. The variant substitutes the nonpolar isoleucine for the polar threonine at an amino acid site that is otherwise highly conserved across placental mammals. By causing the amino acid change, the variant is predicted to subtly alter the structure of the CRIP3 protein. Moreover, the population genetics of the CRIP3 locus reveals an increased frequency of the derived threonine allele of rs2242416 in Eurasian populations following the out-of-Africa migration of humans more than 50,000 years ago. Nevertheless, the role of natural selection in generating this increased allele frequency in Eurasians remains inconclusive. Together, these results provide phenotypic, evolutionary, and molecular context for CRIP3 variation and highlight rs2242416 as a promising candidate for functional studies.Significance Statement Age-related hearing loss is highly prevalent, yet the specific genetic variants that contribute to disease risk remain poorly understood. Here, we investigate a variant (rs2242416) that causes an amino acid change in the CRIP3 gene. While this variant is associated with hearing loss in multiple genome-wide association studies (GWAS), virtually no focused attention has been given to it. By integrating GWAS findings with evolutionary and population genetic analyses, we provide broader context for interpreting this variant. Our results support rs2242416 as a candidate functional variant increasing hearing loss risk in humans. Overall, this study demonstrates the value of combining population genetics with human GWAS to prioritize variants for functional validation.