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; 22.5× WGS) and Pomak (n = 1537; 18.4× 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.

Anogia Medical Centre Anogia 74150 Greece

Centre for Global Health Research Usher Institute University of Edinburgh Edinburgh EH8 9QN UK

Chair of Experimental Genetics TUM School of Life Sciences Technical University of Munich Freising 80333 Germany

Department of Nutrition and Dietetics School of Health Science and Education Harokopio University of Athens Athens 17671 Greece

Echinos Medical Centre Echinos 67300 Greece

German Center for Diabetes Research Neuherberg 40225 Germany

Institute for Pathobiochemistry University Medical Center of the Johannes Gutenberg University Mainz Mainz 55122 Germany

Institute of Biochemistry Unit for Degradomics of the Protease Web University of Kiel Kiel 24118 Germany

Institute of Experimental Genetics German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg 85764 Germany

Institute of Molecular Animal Breeding and Biotechnology Gene Center Ludwig Maximilians University Munich Munich 80539 Germany

Institute of Molecular Genetics of the Czech Academy of Sciences Czech Centre for Phenogenomics Vestec 25250 Czech Republic

Institute of Translational Genomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg 85764 Germany

MRC Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh EH8 9QN UK

Technical University of Munich and Klinikum Rechts der Isar TUM School of Medicine Munich 80333 Germany

Technical University of Munich School of Medicine Munich 80333 Germany

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