GENOME-WIDE ASSOCIATION STUDY IMPLICATES LIPID PATHWAY DYSFUNCTION IN ANTIPSYCHOTIC INDUCED WEIGHT GAIN: MULTI- ANCESTRY VALIDATION

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to type 2 diabetes (T2D) and coronary heart disease.

The aim of this study is to identify genetic predictors and expand the unclear genetic mechanism underlying AIWG.

A two-stage genome-wide association study and polygenic risk score (PRS) profiling for AIWG were conducted with three randomized trials, including a discovery cohort of 1,936 schizophrenia patients, a validated cohort of 534 schizophrenia patients, and an external validation of 630 schizophrenia patients from the CATIE study. We applied Mendelian randomization (MR) to investigate the relationship between AIWG and antipsychotic-induced lipid changes (AILCs). A prediction model for AIWG was developed by combining PRS, AILC, and clinical predictors.

Our results identified novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P=1.373×10-9) and rs3824417 in PTPRD (P=3.348×10-9). The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. PRSs for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P=7.58×10−4) and triglycerides (P=2.06×10−3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating PRSs, AILCs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC=0.79, R2=0.332).

Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.