Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US
Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US
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DOI：
10.1016/j.ajhg.2020.06.009
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发表时间：
2020-08-06
影响因子：
9.8
通讯作者：
Van Hout, Cristopher V.
中科院分区：
文献类型：
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作者：
Kim, Hye In;Ye, Bin;Van Hout, Cristopher V.
将外显子组测序应用于具有独特遗传结构的人群，有可能揭示与性状和疾病相关的新基因和变异。我们对来自西南美洲印第安人（SWAI）人群的6，716名具有良好代谢特征的个体的外显子组进行了测序和分析。我们发现，SWAI人口具有独特的等位基因结构相比，欧洲和东亚血统的人口，有许多预测的功能丧失（pLOF）和非同义变异，高度富集或私人的SWAI人口。我们在SWAI人群中使用pLOF和非同义变异来评估来自欧洲全基因组关联研究（GWAS）的候选基因与2型糖尿病、体重指数和四种主要血脂的基因负荷相关性。我们发现了11个基因的19个显著的基因负担相关性，为优先考虑GWAS信号的候选效应基因提供了额外的证据。有趣的是，这些关联主要是由pLOF和非同义变异驱动的，这些变异在SWAI人群中是独特的或高度富集的。特别是，我们发现APOB，APOE，PCSK9和TM6SF2中的四种pLOF或非同义变体，它们在SWAI人群中是私有的或富集的，并与低密度脂蛋白（LDL）胆固醇水平相关。它们对LDL胆固醇水平的巨大估计影响表明对蛋白质功能的强烈影响以及这些变体在心血管健康中的潜在临床意义。总之，我们的研究说明了外显子组测序在遗传独特人群（如SWAI人群）中的实用性和潜力，以优先考虑GWAS基因座内的候选效应基因，并在已知疾病基因中发现具有潜在临床影响的其他变体。
Applying exome sequencing to populations with unique genetic architecture has the potential to reveal novel genes and variants associated with traits and diseases. We sequenced and analyzed the exomes of 6,716 individuals from a Southwestern American Indian (SWAI) population with well-characterized metabolic traits. We found that the SWAI population has distinct allelic architecture compared to populations of European and East Asian ancestry, and there were many predicted loss-of-function (pLOF) and nonsynonymous variants that were highly enriched or private in the SWAI population. We used pLOF and nonsynonymous variants in the SWAI population to evaluate gene-burden associations of candidate genes from European genome-wide association studies (GWASs) for type 2 diabetes, body mass index, and four major plasma lipids. We found 19 significant gene-burden associations for 11 genes, providing additional evidence for prioritizing candidate effector genes of GWAS signals. Interestingly, these associations were mainly driven by pLOF and nonsynonymous variants that are unique or highly enriched in the SWAI population. Particularly, we found four pLOF or nonsynonymous variants in APOB, APOE, PCSK9, and TM6SF2 that are private or enriched in the SWAI population and associated with low-density lipoprotein (LDL) cholesterol levels. Their large estimated effects on LDL cholesterol levels suggest strong impacts on protein function and potential clinical implications of these variants in cardiovascular health. In summary, our study illustrates the utility and potential of exome sequencing in genetically unique populations, such as the SWAI population, to prioritize candidate effector genes within GWAS loci and to find additional variants in known disease genes with potential clinical impact.