Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers
Dennis van der Meer, Zillur Rahman, Aigar Ottas, Pravesh Parekh, Gleda Kutrolli, Sara Stinson, Maria Koromina, Jaroslav Rokicki, Ida E. Sønderby, Nadine Parker, Markos Tesfaye, Guy Hindley, Linn Rødevand, Elise Koch, Andres Metspalu, Tõnu Esko, Reedik Mägi, Mait Metspalu, Mari Nelis, Georgi Hudjashov, Priit Palta, Nele Taba, Erik Abner, Jaanika Kronberg, Urmo Võsa, Nils Eiel Steen, Jens Petter Berg, Kevin S. O’Connell, Olav B. Smeland, Oleksandr Frei, Anders M. Dale, Srdjan Djurovic, Kelli Lehto, Maris Alver, Lili Milani, Alexey Shadrin, Ole A. Andreassen
Abstract
Metabolites in plasma form biosignatures of a range of common complex human diseases. Discovering variants with pleiotropic effects across metabolites can reveal underlying biological mechanisms. We therefore performed uni- and multivariate genome-wide association studies (GWAS) on 249 circulating metabolic markers across 328,006 UK Biobank and Estonian Biobank participants. We investigated rare variation through whole exome sequencing gene burden tests, analysed the role of body mass index through Mendelian randomization, and performed genome-wide interaction analyses with sex. We discovered 15,585 loci summed over the univariate GWAS, with high pleiotropy across markers, linked to a wide range of disorders. Findings from common and rare variant gene tests converged on lipid homeostasis pathways. 31 loci interacted with sex, mapped to genes involved in cholesterol processing. The findings offer insights into the genetic architecture of circulating metabolites, revealing pleiotropic loci, highlighting the role of rare variation, and uncovering sex-specific molecular mechanisms of lipid metabolism. Circulating metabolites reflect complex disease risk and are shaped by diverse genetic factors. Here, the authors show widespread pleiotropy across 249 metabolic traits, identify rare variant and sex-specific effects, and implicate lipid-related pathways in metabolism.