Exome sequencing and metabolite profiling identifies genetic variants associated with altered metabolism in...

Early-onset schizophrenia (EOS) is a severe psychiatric disorder characterized by strong genetic contribution and metabolic alterations, including lipid dysregulation. To investigate the relationship between genetic variation and metabolic changes in EOS, we performed whole-exome sequencing and serum metabolome profiling in 28 patients with EOS and 20 healthy controls. We identified 114 high-risk genes and 117 differentially expressed metabolites. Of the risk genes with variants in multiple patients, 54.35% (25/46) were associated with clinical symptoms, and of the differentially expressed lipids, 34.88% (15/43) were correlated with clinical symptoms. By integrating protein-metabolite interactions and metabolite correlations, we constructed a gene-metabolite network and identified 19 high-risk genes linking to 31 dysregulated lipids. Twenty of these lipids were significantly down-regulated in patients, with 80% (16/20) showing further down-regulation in variant carriers. Our findings provide compelling evidence for a genetic-metabolic interaction in EOS pathogenesis and point to an alternative disease mechanism of schizophrenia.