The Shared Genetic Etiology of Antisocial Behaviour, Schizophrenia, Substance use and Related Brain Morphology

Brisbane Convention & Exhibition Centre 

Individuals with antisocial behaviour (ASB) exhibit increased risk of substance use disorders, likely linked to shared genetic vulnerabilities and overlapping neural pathways involved in reward processing and impulse control. This susceptibility is further accentuated by the comorbidity of ASB with various psychiatric disorders, suggesting common genetic underpinnings. Despite this there remains a paucity of work examining the shared genetic etiology of ASB, related neuropsychiatric traits and relevant brain regions.
Here we present how combining GWAS of ASB (n=50,252), surface area and thickness of cortical frontal regions, volumes of the amygdala nuclei, psychiatric and substance use phenotypes, and Linkage Disequilibrium Score Regression (LDSC) can be used to assess the genetic correlation between these phenotypes. We then leveraged genetic overlap to boost discovery of genomic loci associated with ASB, and to identify specific shared loci associated with both ASB and each phenotype, using the conditional/conjunctional false discovery rate (cond/conjFDR) approach.
We identified significant genetic correlations between ASPD and drinks per week (rg= 0.28; p=1.33⨉10-9), cannabis (rg= 0.37; p= 1.91⨉10-8), bipolar disorder (BD, rg= 0.20; p=1.95⨉10-5), major depressive disorder (MDD, rg= 0.53; p=1.09⨉10-15) and marginally significant correlations with caudal anterior cingulate surface area (rg=-0.17; p=0.04), superior frontal surface area (rg=0.18; p=0.03), and global measures of cortical surface area (rg=-0.15 ; p=0.02) and thickness (rg=-0.13 ; p=004) and ICV (rg=-0.2 ; p=0.01). A total of 54 loci, representing 127 independent SNPs, became significant after conditioning on related psychiatric disorders, substance use traits and the corpus callosum. These SNPs have been associated with schizophrenia, disruptive behaviour, risk raking behaviours, substance use disorders and cortical surface area in prior GWAS. Two biological processes were implicated: ethanol oxidation and metabolism.
Our results reveal a complex genetic relationship between substance use, psychiatric traits, and ASB. We provide strong evidence for existence of distinct genetic loci exhibiting pleiotropic effects in both ASB and related traits. The findings provide convergent evidence to suggest that substance use traits and psychiatric disorders have shared genetic underpinnings with ASB.