Identifying Causal Serum Protein-Cardiometabolic Trait Relationships Using Whole Genome Sequencing

Grace Png,Raffaele Gerlini，Arthur Gilly,Eleftheria Zeggini

Human Molecular Genetics（2023）SCI 2区

Cited 5|Views37

Abstract

Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 248 serum proteins relevant to cardiometabolic processes in 2893 individuals. Meta-analyzing whole-genome sequencing (WGS) data from two Greek cohorts, MANOLIS (n = 1356; 22.5x WGS) and Pomak (n = 1537; 18.4x WGS), we detect 301 independently associated pQTL variants for 170 proteins, including 12 rare variants (minor allele frequency < 1%). We additionally find 15 pQTL variants that are rare in non-Finnish European populations but have drifted up in the frequency in the discovery cohorts here. We identify proteins causally associated with cardiometabolic traits, including Mep1b for high-density lipoprotein (HDL) levels, and describe a knock-out (KO) Mep1b mouse model. Our findings furnish insights into the genetic architecture of the serum proteome, identify new protein-disease relationships and demonstrate the importance of isolated populations in pQTL analysis.

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Key words

Gene Set Enrichment Analysis,QTL Mapping,Genome-wide Association Studies,Genetic Mapping,Genomic Data Integration

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【要点】：本研究通过全基因组测序识别与cardiometabolic疾病相关的因果血清蛋白调控，发现了302个与255个血清蛋白相关的独立pQTL变异，并确定MEP1B蛋白与高密度脂蛋白水平之间的因果关系。

【方法】：研究者采用了蛋白定量性状位点（pQTL）分析，对2893名个体中与cardiometabolic过程相关的255个血清蛋白进行了分析。

【实验】：通过分析两个希腊队列（MANOLIS和Pomak）的全基因组测序（WGS）数据，共检测到302个独立关联的pQTL变异与171个蛋白质相关，包括12个罕见变异。研究还发现15个在非芬兰欧洲人群中罕见的pQTL变异，但在发现队列中频率上升。研究者确定了与cardiometabolic特征因果相关的蛋白，如MEP1B与高密度脂蛋白水平的关系，并描述了敲除Mep1b的小鼠模型。