Identifying causal serum protein-cardiometabolic trait relationships using whole genome sequencing

Png, Grace; Gerlini, Raffaele; Hatzikotoulas, Konstantinos; Barysenka, Andrei; Rayner, N. William; Klaric, Lucija; Rathkolb, Birgit; Aguilar-Pimentel, Juan A.; Rozman, Jan; Fuchs, Helmut; Gailus-Durner, Valerie; Tsafantakis, Emmanouil; Karaleftheri, Maria; Dedoussis, George; Pietrzik, Claus; Wilson, James F.; Hrabe de Angelis, Martin; Becker-Pauly, Christoph; Gilly, Arthur und Zeggini, Eleftheria (2022): Identifying causal serum protein-cardiometabolic trait relationships using whole genome sequencing. In: Human Molecular Genetics, Bd. 32, Nr. 8: S. 1266-1275

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Tiermedizin > Veterinärwissenschaftliches Department
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0964-6906
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 125440785