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新研究系统性揭示稀有的编码变异关联
2021-07-08 17:06

美国哈佛医学院Po-Ru Loh、Alison R. Barton等研究人员合作系统性揭示稀有的编码变异关联。该项研究成果于2021年7月5日在线发表在《自然—遗传学》杂志上。

研究人员利用49,960名外显子组测序的UK Biobank参与者和队列的其余部分(总数≈500,000)之间的广泛单倍型共享,来估算了外显子组范围的变异(准确度R2>0.5,次等位基因频率(MAF)约为0.00005 )。对54个数量性状的关联和精细定位分析确定了1,189个显著关联(P<5×10-8),涉及675个不同的稀有蛋白质改变变体(MAF<0.01),它们通过了可能的因果关系的严格筛选。在所有性状中,49%的关联(578/1,189)发生在具有两个或更多命中的基因中;对这些基因的后续分析确定了包含多达45个不同“可能因果”变异的等位基因系列。

这些结果证明了队列内插补在人口规模全基因组关联研究中的实用性,提供了潜在因果关联的、具有较大影响的编码变异关联目录,并预示了随着遗传生物库研究的不断发展将会被揭示的见解。

据了解,迄今为止,外显子组关联研究通常不足以系统地评估非常罕见的编码变异的表型影响。

附:英文原文

Title: Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses

Author: Alison R. Barton, Maxwell A. Sherman, Ronen E. Mukamel, Po-Ru Loh

Issue&Volume: 2021-07-05

Abstract: Exome association studies to date have generally been underpowered to systematically evaluate the phenotypic impact of very rare coding variants. We leveraged extensive haplotype sharing between 49,960 exome-sequenced UK Biobank participants and the remainder of the cohort (total n≈500,000) to impute exome-wide variants with accuracy R2>0.5 down to minor allele frequency (MAF) ~0.00005. Association and fine-mapping analyses of 54 quantitative traits identified 1,189 significant associations (P<5×108) involving 675 distinct rare protein-altering variants (MAF<0.01) that passed stringent filters for likely causality. Across all traits, 49% of associations (578/1,189) occurred in genes with two or more hits; follow-up analyses of these genes identified allelic series containing up to 45 distinct ‘likely-causal’ variants. Our results demonstrate the utility of within-cohort imputation in population-scale genome-wide association studies, provide a catalog of likely-causal, large-effect coding variant associations and foreshadow the insights that will be revealed as genetic biobank studies continue to grow.

DOI: 10.1038/s41588-021-00892-1

Source: https://www.nature.com/articles/s41588-021-00892-1

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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