Disease variants identified by genome-wide association studies (GWAS) tend to overlap with expression quantitative trait loci (eQTLs), but it remains unclear whether this overlap is driven by gene expression levels 'mediating' genetic effects on disease. Here, we introduce a new method, mediated expression score regression (MESC), to estimate disease heritability mediated by the cis genetic component of gene expression levels. We applied MESC to GWAS summary statistics for 42 traits (average N = 323,000) and cis-eQTL summary statistics for 48 tissues from the Genotype-Tissue Expression (GTEx) consortium. Averaging across traits, only 11 ± 2% of heritability was mediated by assayed gene expression levels. Expression-mediated heritability was enriched in genes with evidence of selective constraint and genes with disease-appropriate annotations. Our results demonstrate that assayed bulk tissue eQTLs, although disease relevant, cannot explain the majority of disease heritability.

中文翻译：

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量化由测定的基因表达水平介导的对疾病的遗传影响。

通过全基因组关联研究（GWAS）鉴定出的疾病变体往往与表达定量性状基因座（eQTL）重叠，但是尚不清楚这种重叠是否由基因表达水平“介导”对疾病的遗传效应驱动。在这里，我们介绍了一种新的方法，介导的表达评分回归（MESC），以估计由基因表达水平的顺式遗传成分介导的疾病遗传力。我们将MESC应用于GWAS的42个性状的摘要统计（平均N = 323,000）和来自基因型组织表达（GTEx）联盟的48个组织的cis-eQTL摘要统计。平均所有性状，仅11±2％的遗传力由测定的基因表达水平介导。表达介导的遗传力在具有选择性约束证据的基因和具有疾病适当注释的基因中得到了丰富。我们的结果表明，虽然与疾病相关，但测定的大块组织eQTL不能解释大多数疾病的遗传性。