Multi-omics analysis identifies rare variation in leptin/PPAR gene sets and hypermethylation of ABCG1 contribute to antipsychotics-induced metabolic syndromes

Antipsychotic-induced metabolic syndrome (APs-induced Mets) is the most common adverse drug reaction, which affects more than 60% of the psychiatric patients. Although the etiology of APs-induced Mets has been extensively investigated, there is a lack of integrated analysis of the genetic and epigenetic factors. In this study, we performed genome-wide, whole-exome sequencing (WES) and epigenome-wide association studies in schizophrenia (SCZ) patients with or without APs-induced Mets to find the underlying mechanisms, followed by in vitro and in vivo functional validations. By population-based omics analysis, we revealed that rare functional variants across in the leptin and peroxisome proliferator-activated receptors (PPARs) gene sets were imbalanced with rare functional variants across the APs-induced Mets and Non-Mets cohort. Besides, we discovered that APs-induced Mets are hypermethylated in ABCG1 (chr21:43642166-43642366, adjusted P < 0.05) than Non-Mets, and hypermethylation of this area was associated with higher TC (total cholesterol) and TG (triglycerides) levels in HepG2 cells. Candidate genes from omics studies were furtherly screened in C. elegans and 17 gene have been verified to associated with olanzapine (OLA) induced fat deposit. Among them, several genes were expressed differentially in Mets cohort and APs-induced in vitro/in vivo models compared to controls, demonstrating the validity of omics study. Overexpression one of the most significant gene, PTPN11, exhibited compromised glucose responses and insulin resistance. Pharmacologic inhibition of PTPN11 protected HepG2 cell from APs-induced insulin resistance. These findings provide important insights into our understanding of the mechanism of the APs-induced Mets.

Automated summary

In this study, the genetic and epigenetic factors of antipsychotic-induced metabolic syndrome were analyzed through genome-wide and whole-exome sequencing as well as epigenome-wide association studies. The findings suggest an imbalance of rare functional variants in the leptin and peroxisome proliferator-activated receptors gene sets between the APs-induced Mets and Non-Mets cohorts. Moreover, hypermethylation in ABCG1 region was associated with higher TC and TG levels, and several candidate genes were verified to be associated with olanzapine-induced fat deposit. Overexpression of PTPN11 gene resulted in compromised glucose responses and insulin resistance, which could be protected by pharmacologic inhibition of PTPN11.