Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins. We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F). Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.

中文翻译：

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92 种循环蛋白的蛋白质组学分析及其在心脏代谢疾病中的作用

人血浆含有多种循环蛋白。这些蛋白质可能是疾病的重要临床生物标志物，也是可能的药物靶点。对循环蛋白质的大规模基因组学研究可以识别导致相对蛋白质丰度的遗传变异。我们对 12 个队列的 22,997 名欧洲血统个体的常染色体全基因组关联研究进行了荟萃分析，以确定 92 种心脏代谢相关血浆蛋白的蛋白质数量性状位点 (pQTL)。我们鉴定了 503 个（337 个顺式和 166 个反式）条件独立的 pQTL，包括文献中未报道的几种新变体。我们进行了性别分层分析，发现 118 个 (23.5%) pQTL 在性别之间表现出异质性。效应方向得以保留，但效应大小和显着性存在差异。此外，我们用最近的基因注释反式 pQTL 并报告合理的生物学关系。使用孟德尔随机化，我们确定了 19 个表型中 18 个蛋白质的因果关系，其中 10 个具有额外的遗传共定位证据。我们重点关注与一系列心脏代谢特征相关的蛋白质，包括血管生成素相关蛋白 7 (ANGPTL7) 和信号蛋白 3F (SEMA3F)。通过对蛋白质数量性状基因座的大规模分析，我们提供了与血浆蛋白相关的常见变异的全面概述。我们强调了可能的生物学关系，这可以作为进一步研究心脏代谢疾病中可能的因果作用的基础。