Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
Department of Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
Nat Commun. 2024 Aug 14;15(1):6985. doi: 10.1038/s41467-024-51075-5.
Genome-wide association studies (GWAS) have found widespread evidence of pleiotropy, but characterization of global patterns of pleiotropy remain highly incomplete due to insufficient power of current approaches. We develop fastASSET, a method that allows efficient detection of variant-level pleiotropic association across many traits. We analyze GWAS summary statistics of 116 complex traits of diverse types collected from the GRASP repository and large GWAS Consortia. We identify 2293 independent loci and find that the lead variants in nearly all these loci (~99%) to be associated with traits (median = 6). We observe that degree of pleiotropy estimated from our study predicts that observed in the UK Biobank for a much larger number of traits (K = 4114) (correlation = 0.43, p-value ). Follow-up analyzes of 21 trait-specific variants indicate their link to the expression in trait-related tissues for a small number of genes involved in relevant biological processes. Our findings provide deeper insight into the nature of pleiotropy and leads to identification of highly trait-specific susceptibility variants.
全基因组关联研究（GWAS）已经发现了广泛的多效性证据，但由于当前方法的能力不足，对多效性的全局模式的描述仍然非常不完整。我们开发了 fastASSET 方法，该方法允许在许多性状中高效检测变异水平的多效性关联。我们分析了来自 GRASP 存储库和大型 GWAS 联盟的 116 种不同类型的复杂性状的 GWAS 汇总统计数据。我们确定了 2293 个独立的基因座，并发现几乎所有这些基因座（~99%）的主要变异与性状有关（中位数=6）。我们观察到，从我们的研究中估计的多效性程度与英国生物库中更大数量的性状（K=4114）的观察结果相关（相关性=0.43，p 值<0.0001）。对 21 个特定于性状的变体的后续分析表明，它们与参与相关生物学过程的少数基因在性状相关组织中的表达有关。我们的发现提供了对多效性性质的更深入了解，并导致了对高度特定于性状的易感性变体的鉴定。
