Integrative exome sequencing and multi-omics analysis elucidates the regulatory role of rare variants in metabolic syndrome.

Metabolic syndrome (MetS) is a cluster of interconnected cardiometabolic risk factors with a substantial but incompletely characterized genetic basis. To identify novel genetic determinants, particularly rare variants, we here conducted a large-scale exome-wide association study in 367,188 individuals from the UK Biobank (78,300 cases and 288,888 controls). Single-variant analysis identified 74 independent loci, three of which correspond to rare variants in CARMIL2, ACTR6, and PLA2G12A without prior documented MetS association. Furthermore, gene-based burden testing pinpointed three key genes: ABCA1, APOC3, and PDE3B. Integrative follow-up analyses - including colocalization across molecular traits (mRNA, protein, microbiota) and association testing with proteomic/metabolic biomarkers - collectively suggest that these rare variants influence MetS susceptibility through coordinated effects on protein expression, metabolite concentrations, and microbial abundance. Importantly, ABCA1, APOC3, and PDE3B are established or promising drug targets for related metabolic disorders. In summary, our study not only elucidates the significant contribution of rare variants to MetS susceptibility, distinct from common variant signals, but also highlights the central role of lipid metabolism pathways, thereby nominating plausible targets for therapeutic intervention. Clinical trial number:Not applicable.