Identifying causal serum protein–cardiometabolic trait relationships using whole genome sequencing
Year: 2022
Type: article
Study design: Observational Study
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; 22.5× 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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddac275
Authors: Grace Png, Raffaele Gerlini, Konstantinos Hatzikotoulas, Andrei Barysenka, N William Rayner, Lucija Klarić, Birgit Rathkolb, Juan A Aguilar-Pimentel, Jan Rozman, Helmut Fuchs, Valerie Gailus-Durner, Emmanouil Tsafantakis, Maria Karaleftheri, George Dedoussis, Claus Pietrzik, James F Wilson, Martin Hrabe de Angelis, Christoph Becker-Pauly, Arthur Gilly, Eleftheria Zeggini
Institutions: Helmholtz Munich, Technical University of Munich, German Center for Diabetes Research, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, Ludwig-Maximilians-Universität München, Czech Academy of Sciences, Czech Academy of Sciences, Institute of Molecular Genetics, Czech Centre for Phenogenomics, Ankang City Central Hospital, Harokopio University of Athens, Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz, Christian-Albrechts-Universität zu Kiel, TUM Klinikum
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,181
Funders: Wellcome Trust, Scottish Government, Broad Institute, INFRAFRONTIER, Arthritis Research UK, Research Councils UK, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Versus Arthritis, Medical Research Council, European Research Council, Deutsches Zentrum für Diabetesforschung
Awards: G1212304895, G1689944598, G191003546, G2058654086, G2513189564, G2525055934, G2693665147, G2951182233, G3001543491, G3263306511, G4663499900, Determining the causal links and clinical significance of rare genetic variants, G4801199537, G4839860845, G4871145473, SFB 877: Proteolyse als regulatorisches Ereignis in der Pathophysiologie, G5597712516, G5768992294, Quantitative Traits in Health and Disease, G6260303519, Aufbau und Implementierung der deutschen Infrafrontier-Einrichtungen - Implementierungsphase 2, G6668520876, G8330560607, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers, G970400076
OpenAlex ID: W4308603268