PDF(Pubmed)
Abstract：
Complex traits are characterized by multiple genes and variants acting simultaneously on a phenotype. However, studying the contribution of individual pairs of genes to complex traits has been challenging since human genetics necessitates very large population sizes, while findings from model systems do not always translate to humans. Here, we combine genetics with combinatorial RNAi (coRNAi) to systematically test for pairwise additive effects (AEs) and genetic interactions (GIs) between 30 lipid genome-wide association studies (GWAS) genes. Gene-based burden tests from 240,970 exomes show that in carriers with truncating mutations in both, APOB and either PCSK9 or LPL (\"human double knock-outs\") plasma lipid levels change additively. Genetics and coRNAi identify overlapping AEs for 12 additional gene pairs. Overlapping GIs are observed for TOMM40/APOE with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate plasma and cellular lipid levels primarily via AEs and nominates putative drug target pairs for improved lipid-lowering combination therapies.
摘要：
复杂性状的特征在于多个基因和变体同时作用于表型。然而,由于人类遗传学需要非常大的种群规模，因此研究单个基因对复杂性状的贡献一直具有挑战性，虽然模型系统的发现并不总是能转化为人类。这里,我们将遗传学与组合RNAi(coRNAi)相结合,系统地检测了30个脂质全基因组关联研究(GWAS)基因之间的成对加性效应(AE)和遗传相互作用(GI).来自240,970个外显子组的基于基因的负担测试表明，在两者都具有截断突变的携带者中，APOB和PCSK9或LPL（“人类双重敲除”）血浆脂质水平增加变化。遗传学和coRNAi鉴定了12个另外的基因对的重叠AE。对于具有SORT1和NCAN的TOMM40/APOE,观察到重叠的GI。我们的研究确定了主要通过AE调节血浆和细胞脂质水平的不同基因对，并提名了用于改善降脂联合疗法的推定药物靶标对。
