Cross-disorder GWAS meta-analysis of endocannabinoid DNA variations in major depressive disorder, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorder, and schizophrenia

Abstract

The endocannabinoid system (ECS) is implicated in multiple mental disorders. In this study, we explored DNA variations in the ECS across major depressive disorder (MDD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia by performing a cross-disorder genome-wide association study (GWAS) meta-analysis. We obtained six datasets from the Psychiatric Genomics Consortium containing GWAS summary statistics from European cohorts (284,023 cases and 508,515 controls). Effective sample size weighted meta-analysis was performed for 2241 single nucleotide polymorphisms (SNPs) pertaining to gene bodies of 33 endocannabinoid genes using METAL, where an overall z-statistic is calculated for each marker based on a weighted sum of individual statistics. Heterogeneity was examined with I² and X² tests. MAGMA gene-based analysis was also performed. We identified nine SNPs significantly associated with a change in risk of having a mental disorder. The lead SNP was rs12805732 (Gene: Diacylglycerol Lipase Alpha; DAGLA). Four SNPs had substantial heterogeneity (I²>60 %). DAGLA had the strongest association with disease risk in gene-based analysis. Our findings suggest that the ECS may be a shared pathway in mental disorders. Future studies validating these findings would contribute to the identification of biomarkers of disease risk across multiple mental disorders.

Keywords: Cross-disorder; Endocannabinoid system; GWAS, DAGLA, GABRA1; Mental disorder.