- Integrated exome sequencing and serum metabolomics in 28 EOS patients and 20 controls identified 114 high-risk genes and 117 differentially expressed metabolites.
- Fifty-four percent of recurrent variant risk genes and thirty-five percent of dysregulated lipids showed significant correlations with clinical symptoms.
- A gene-metabolite network linked 19 high-risk genes to 31 dysregulated lipids; 20 lipids were down-regulated, 16 further reduced in variant carriers.
iScience. 2026 Aug 11;29(8):117123. doi: 10.1016/j.isci.2026.117123. eCollection 2026 Aug 21.
ABSTRACT
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.
PMID:42620925 | PMC:PMC13487321 | DOI:10.1016/j.isci.2026.117123
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