Partitioning gene-level contributions to complex-trait heritability by allele frequency identifies disease-relevant genes.
Partitioning gene-level contributions to complex-trait heritability by allele frequency identifies disease-relevant genes.
复制标题
通过等位基因频率划分基因水平对复杂性状遗传力的贡献，可以识别疾病相关基因。
DOI：
10.1016/j.ajhg.2022.02.012
复制
发表时间：
2022
影响因子：
9.8
通讯作者：
Pasaniuc,Bogdan
中科院分区：
文献类型：
--
作者：
Burch,KathrynS;Hou,Kangcheng;Ding,Yi;Wang,Yifei;Gazal,Steven;Shi,Huwenbo;Pasaniuc,Bogdan
最近的研究表明，SNP遗传率——由低效应的常见变异主导——可能不是定位高效应/关键疾病基因的最相关的数量。在这里，我们介绍了一些方法来估计由单个基因的给定snp分配所解释的表型变异比例（“基因水平遗传力”）。我们通过小等位基因频率（minor allele frequency， MAF）划分基因水平遗传力，以寻找那些基因水平遗传力完全由“低频/罕见”变异（0.5%≤MAF < 1%）解释的基因。将我们的方法应用于UK Biobank （N = 290K“White British”）中的约16K蛋白质编码基因和25个数量性状，我们发现，在性状中，平均而言，约2.5%的非零遗传力基因具有罕见变异成分，只有约0.8%（327对基因-性状）具有完全来自罕见变异的遗传力。在这327对基因性状对中，114对（35%）未被现有的基因水平关联检测方法检测到。我们发现的其他基因在已知的疾病基因中显著富集，并且我们发现了一些先前与表型相关的孟德尔疾病有关的基因的例子。值得注意的是，基因水平遗传力的罕见变异成分表现出不同于常见变异基因水平遗传力的趋势。例如，虽然总基因水平遗传力随着基因长度的增加而增加，但在较短的基因中，罕见变异成分明显更大；基因水平遗传力的累积分布也因性状而异，并揭示了罕见/常见变异对总体基因水平多基因性的相对贡献的差异。虽然非零基因水平遗传力并不意味着因果关系，但如果在正确的背景下解释，基因水平遗传力可以揭示对复杂性状遗传结构的有用见解。
Recent works have shown that SNP heritability—which is dominated by low-effect common variants—may not be the most relevant quantity for localizing high-effect/critical disease genes. Here, we introduce methods to estimate the proportion of phenotypic variance explained by a given assignment of SNPs to a single gene ("gene-level heritability"). We partition gene-level heritability by minor allele frequency (MAF) to find genes whose gene-level heritability is explained exclusively by "low-frequency/rare" variants (0.5% ≤ MAF < 1%). Applying our method to ∼16K protein-coding genes and 25 quantitative traits in the UK Biobank (N = 290K "White British"), we find that, on average across traits, ∼2.5% of nonzero-heritability genes have a rare-variant component and only ∼0.8% (327 gene-trait pairs) have heritability exclusively from rare variants. Of these 327 gene-trait pairs, 114 (35%) were not detected by existing gene-level association testing methods. The additional genes we identify are significantly enriched for known disease genes, and we find several examples of genes that have been previously implicated in phenotypically related Mendelian disorders. Notably, the rare-variant component of gene-level heritability exhibits trends different from those of common-variant gene-level heritability. For example, while total gene-level heritability increases with gene length, the rare-variant component is significantly larger among shorter genes; the cumulative distributions of gene-level heritability also vary across traits and reveal differences in the relative contributions of rare/common variants to overall gene-level polygenicity. While nonzero gene-level heritability does not imply causality, if interpreted in the correct context, gene-level heritability can reveal useful insights into complex-trait genetic architecture.