小柯机器人

美国麻省理工学院和哈佛大学的布罗德研究所Luke J. O’Connor、Ajay Nadig和Daniel J. Weiner共同合作，近期取得重要工作进展。他们研究发现了394783个外显子的罕见编码变异的多基因结构。相关研究成果2023年2月8日在线发表于《自然》杂志上。

据介绍，常见和罕见的遗传变异都会影响复杂的性状和常见疾病。全基因组关联研究已经确定了数千种常见的变异关联，最近，大规模的外显子组测序研究已经在数百种基因中确定了罕见的变异关联。然而，罕见变异基因结构没有很好的表征，常见变异和罕见变异结构之间的关系尚不清楚。

研究人员量化了394783个英国生物库外显子5中22个常见性状和疾病的罕见编码变异的基因负荷所解释的遗传力。罕见的编码变异（等位基因频率<1×10⁻³）解释了平均1.3%（s.e=0.03%）的表型变异，远低于常见变异，大多数负担遗传力是由超罕见的功能丧失变异（等位基因频率<1×10⁻⁵）解释的。常见和罕见的变异涉及相同的细胞类型，具有相似的丰度，它们对相同的成对性状具有多效性，具有相似遗传相关性。它们在单个基因和基因座上部分共定位，但程度不同：负担遗传力强烈集中在显著基因中，而共同变异遗传力更为多基因，负担遗传力也更强烈集中在受约束基因中。最后，研究人员发现精神分裂症和双相情感障碍的负担遗传力约为2%。

总之，这一结果表明，罕见的编码变异将涉及大量的大效应基因，常见和罕见的关联在机制上是趋同的，罕见的基因编码变异只会对缺失遗传力和人群风险分层产生轻微的影响。

附：英文原文

Title: Polygenic architecture of rare coding variation across 394,783 exomes

Author: Weiner, Daniel J., Nadig, Ajay, Jagadeesh, Karthik A., Dey, Kushal K., Neale, Benjamin M., Robinson, Elise B., Karczewski, Konrad J., OConnor, Luke J.

Issue&Volume: 2023-02-08

Abstract: Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes1,2,3. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear4. Here we quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes5. Rare coding variants (allele frequency<1×103) explain 1.3% (s.e.=0.03%) of phenotypic variance on average—much less than common variants—and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency<1×105). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in significant genes, while common-variant heritability is more polygenic, and burden heritability is also more strongly concentrated in constrained genes. Finally, we find that burden heritability for schizophrenia and bipolar disorder6,7 is approximately 2%. Our results indicate that rare coding variants will implicate a tractable number of large-effect genes, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.

DOI: 10.1038/s41586-022-05684-z

Source: https://www.nature.com/articles/s41586-022-05684-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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