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

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 I ² and X ² 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 (I ² >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.
Competing Interests: Declaration of Competing Interest MIH receives research support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research (CIHR), CAMH Foundation, the Physicians’ Services Incorporated (PSI) Foundation, and the University of Toronto. He has provided consultancy to Mindset Pharma, PsychEd Therapeutics, and Wake Network. He has led contracted research for COMPASS Pathways Ltd. DJM's research work is supported by the Canadian Institutes of Health Research (CIHR), the Ontario Brain Foundation, the Alternate Funding Plan of Ontario, and the Centre for Addiction and Mental Health Foundation. BHM holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received within the past five years research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He has also been an unpaid consultant to Myriad Neuroscience. GZ's work has been supported by the Academic Scholar Award and the Labatt Family Innovation Fund in Brain Health, Department of Psychiatry, University of Toronto in addition to the Brain & Behavior Research Foundation, International Obsessive-Compulsive Disorder Foundation, and PSI Foundation in Ontario, Canada. SK's work has been supported by the Academic Scholar Award and the Labatt Family Innovation Fund in Brain Health, Department of Psychiatry, University of Toronto. SK has also received honorarium for past consultation from EmpowerPharm. HKK and VFG have no conflict of interest to disclose.
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