Antipsychotic – induced weight gain (AIWG) is a significant concern in psychiatric treatment, as it increases the risk of cardiovascular diseases. During the acute – phase treatment, the weight gain caused by atypical antipsychotic drugs can elevate the risk of cardiovascular diseases by approximately 1.05 – 9.33%. Moreover, AIWG often occurs simultaneously with metabolic disorders induced by antipsychotic drugs, further escalating the cardiovascular risk for patients. Thus, preventing or intervening in AIWG in clinical practice is of great significance. Previous studies have indicated that the variability of AIWG is mainly influenced by genetic factors, making it necessary to conduct genetic association studies to explore its genetic mechanisms and promote personalized treatment for schizophrenia.
Recently, a research team led by Professor Yue Weihua from the Sixth Hospital of Peking University published a research paper titled “Genome – wide association study implicates lipid pathway dysfunction in antipsychotic – induced weight gain: multi – ancestry validation” in the internationally renowned journal Molecular Psychiatry. As the largest – scale genome – wide association study on AIWG to date, this research reveals that the genetic mechanism of AIWG is related to the dysfunction of lipid metabolism pathways.
The study first identified that rs10422861 located in the PEPD gene and rs3824417 located in the PTPRD gene are significantly associated with AIWG at the genome – wide level. Subsequently, through fine – mapping and functional annotation, the researchers explored the causative genes, localizing rs10422861 and rs3824417 to genes in lipid – related pathways. These pathways involve the differentiation of white and brown adipocytes and the transcriptional cascade regulating adipogenesis. Functional annotation shows that rs10422861 may exert its effect on AIWG by regulating multiple molecular phenotypes of the PEPD gene in the blood and brain, including DNA methylation, RNA levels, and alternative polyadenylation. Compared with non – homozygous allele carriers, homozygous allele carriers of rs10422861 have stronger functional connections between the right lateral hypothalamus and the right cerebellum. In addition, the study for the first time discovers that AIWG and type 2 diabetes share causal genetic variations in the PEPD gene region.
The research indicates that both the polygenic risk score for AIWG and that for type 2 diabetes are significantly and positively correlated with the risk of AIWG in patients during the acute – phase treatment with antipsychotic drugs. Furthermore, for the first time, the researchers revealed through Mendelian randomization analysis that during antipsychotic drug treatment, a one – unit increase in the log – transformed value of low – density lipoprotein at week 4 leads to a 4.23% increase in BMI at week 6; and a one – unit increase in the log – transformed value of triglyceride levels at week 6 leads to a 1.70% increase in BMI at week 6.
By combining the above – mentioned polygenic risk scores, lipid indicators, and previously reported clinical predictors, the study further constructed a combined prediction model for AIWG with good calibration and discrimination (AUC = 0.79, 95% CI: 0.73 – 0.85). Compared with the pure clinical model, the combined prediction model has higher regression performance (cross – validation R² for the clinical model = 0.298, cross – validation R² for the combined model = 0.332). Decision curve analysis shows that within the risk threshold range of 10% – 100%, the clinical net benefit of this combined prediction model is higher than the strategies of either full treatment or no treatment at all, indicating its potential for precision medicine.
Finally, the study identifies PEPD and PTPRD as candidate intervention targets for AIWG. Drug repositioning analysis suggests that peroxisome proliferator – activated receptor α (PPARα) agonists and triglyceride synthesis inhibitors are potential interventions for AIWG. The protein – protein interaction network (PPI) indicates that PEPD, PTPRD, and PPARα are connected to the proteins encoded by antipsychotic drug targets (DRD2, HTR2C) and previously identified AIWG – susceptible genes (MC4R, LEP, SREBF1, IQSEC1, FTO, INSIG2) through EGFR and SLITRK1.
In conclusion, this research provides new insights into the pathogenesis of AIWG, further reveals the connection between antipsychotic drugs and metabolic disorders, and offers important solutions for the metabolic disorders that occur during the treatment of schizophrenia.
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