Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain:...

Area of Science:

• Pharmacogenomics
• Metabolic Disorders
• Psychiatry

Background:

• Antipsychotic-induced weight gain (AIWG) is a significant clinical challenge, increasing risks for diabetes and heart disease.
• The genetic underpinnings of AIWG remain incompletely understood, necessitating further investigation.

Purpose of the Study:

• To identify novel genetic loci associated with AIWG using a genome-wide association study (GWAS) in Han Chinese schizophrenia patients.
• To explore the role of lipid metabolism in AIWG pathogenesis and its shared genetic basis with type 2 diabetes (T2D).
• To develop a predictive model for AIWG using genetic, lipid, and clinical factors.

Main Methods:

• Two-stage GWAS in Han Chinese patients, followed by validation in European cohorts.
• Mendelian randomization (MR) analysis to assess causal relationships between AIWG, lipid changes, and T2D.
• Fine-mapping, functional annotation, and polygenic risk score (PRS) analysis.

Main Results:

• Two novel loci, rs10422861 in PEPD and rs3824417 in PTPRD, were significantly associated with AIWG.
• PEPD and PTPRD were identified as potential causal genes for AIWG, with rs10422861 validated in European samples.
• AIWG and T2D shared a causal variant in PEPD. Genetically predicted lipid changes (LDL cholesterol, triglycerides) causally influenced AIWG.
• A predictive model incorporating lipid changes, PRSs, and clinical factors achieved high accuracy (AUC=0.79, R²=0.332) for BMI change.

Conclusions:

• AIWG pathogenesis involves lipid pathway dysfunction and shares genetic links with T2D via the PEPD gene.
• PEPD and PTPRD represent promising therapeutic targets for mitigating AIWG.
• The findings support personalized treatment strategies for schizophrenia by integrating genetic risk and metabolic factors.