Mol Psychiatry. 2026 Mar 21. doi: 10.1038/s41380-026-03544-0. Online ahead of print.
ABSTRACT
Antipsychotics-induced metabolic syndrome (APs-induced MetS) is a common side-effect of antipsychotics, significantly increasing the risk of cardiovascular diseases and mortality. However, the genetic risk factors underlying APs-induced MetS remain poorly understood. Thus, we conducted a sex-stratified genome-wide association study (GWAS) in 3067 patients from Schizophrenia In Non-Occidental participants (SINO) trial, and significant results were validated in an independent cohort (all samples = 200) and proteomic data. Post-GWAS analyses were used to further explore the genetic mechanisms involved in APs-induced MetS. Multi-omics prediction incorporating both polygenic risk and proteomic markers was conducted. After quality control, 1956 patients (965 males, 991 females) were included. We identified significant genetic variants (rs73762168; P = 1.77 × 10-8) on chromosome 6q21, associated with three highly linked genes, NR2E1, SNX3 and AFG1L/LACE1, which were correlated with APs-induced MetS in male patients. Top SNP genotype was validated in independent cohort, showing associations with increased weight and waist circumference. Enrichment analyses across genetic and proteomic data consistently highlighted the PPAR signaling pathway involved in oxidative stress and fatty acid metabolism as a key contributor to APs-induced MetS development. Proteomic analyses confirmed baseline SNX3 protein levels associated with weight gain (P = 0.03) and increased waist circumference (P = 8.87 × 10-3) following six-week antipsychotic treatment. The multi-omics prediction (R2 = 0.18) yielded better prediction of APs-induced metabolic side effects than using either marker alone(R2 = 0.13 or 0.07). This study provides novel genetic insights into the development of APs-induced MetS, particularly in males. The identified genetic variants and pathways offer potential targets for early risk prediction and personalized treatment strategies.
PMID:41865124 | DOI:10.1038/s41380-026-03544-0