Pleiotropic and sex-specific genetic architecture of circulating metabolic markers

Background: Metabolites in plasma form biosignatures of a range of common complex human diseases. Mapping the genetic architecture and discovering variants with pleiotropic effects across metabolites can reveal underlying mechanisms and potential targets for personalized interventions. Methods: We performed univariate and multivariate genome-wide association studies (GWAS) on the Nightingale panel of 249 circulating plasma metabolic markers, across 207,836 White British UK Biobank participants (mean age 57.4 years, 53.7% female), with replication conducted across 27,509 UK Biobank participants with different ancestries, and 92,661 Estonian Biobank participants (mean age 50.9 years, 65.7% female). We investigated rare variation through whole exome sequencing gene burden tests, quantified genetic architectures through Gaussian mixture modelling, analysed the causal role of body mass index (BMI) through Mendelian randomization, and performed genome-wide interaction analyses with sex. Results: We discovered 14,837 loci (497 unique), with shared and distinct effects on cardiometabolic traits, with high replication rates across populations. The loci explained over 70% of genetic variance for fatty acids. Findings from common and rare variant gene tests converged on lipid homeostasis pathways. There was strong evidence for causal effects of BMI on cholesterol and amino acid levels. We discovered 31 loci interacting with sex, which mapped to genes involved in cholesterol processing, and to cardiometabolic conditions with sex differences in prevalence. Discussion: The findings offer new insights into the genetic architecture of circulating metabolites, revealing novel loci and plausible sex-specific molecular mechanisms of lipid metabolism. This improved understanding of the molecular biology of metabolism lays a foundation for personalized prevention and treatment strategies.