32. GENOME-WIDE ASSOCIATION STUDY OF SEVERE EXTERNALIZING PSYCHOPATHOLOGY IDENTIFIES SIGNIFICANT RISK LOCI AND IMPLICATE BIOLOGICAL PROCESSES IN DOPAMINERGIC NEURONS

Background Severe externalizing psychopathology (SEP), including childhood-onset disruptive behaviour disorders (DBDs) and adult diagnoses such as dissocial personality disorder and emotionally unstable personality disorder, is associated with a range of adverse outcomes. However, the genetic architecture of clinically diagnosed SEP remains under investigated, and the role of genetic liability in the developmental trajectory from childhood DBDs to adult antisocial psychopathology has not been well characterized. Here, we present results from an ongoing GWAS meta-analysis of SEP involving data from multiple contributing sites. Methods In this study we included individuals diagnosed with DBDs (ICD-10 F90.1, F91.0–F91.9), dissocial personality disorder (ICD-10 F60.2), and emotionally unstable personality disorder (ICD-10 F60.3), in multiple cohorts including iPSYCH, Million Veteran Project, FinnGen, deCODE, All of Us, and six PGC cohorts. We aim to identify associated risk loci through GWAS meta-analysis, map credible variants to genes using FLAMES, and prioritize relevant tissues and cell types using approaches including LDSC partitioned heritability and single-cell disease relevance score (scDRS) analyses. In addition, we will perform polygenic score (PGS) analyses in the ABCD cohort to evaluate whether the GWAS results capture liability to childhood aggression in an independent cohort. We will also use single-cell RNA-sequencing data from 173 iPSC donors to identify genes whose expression in midbrain neuronal cells is associated with the SEP-PGS across different neuronal developmental stages. Finally, we will estimate the absolute risk of receiving an adult diagnosis of dissocial personality disorder or emotionally unstable personality disorder among individuals diagnosed with DBDs in childhood. Results We observed high positive genetic correlations among DBDs, dissocial personality disorder, and emotionally unstable personality disorder (rg = 0.86–1.00), supporting that these diagnoses share substantial common genetic liability and can be jointly analysed to capture a broadly defined SEP. In the preliminary GWAS meta-analysis, comprising 30K cases and > 1M controls, we identified 21 genome-wide significant loci. Associated variants were linked to genes with enriched expression in brain tissue, and scDRS analyses implicated genes expressed in GABAergic and dopaminergic midbrain neurons. In analyses of the 173 iPSC donors, the SEP-PGS was significantly associated with expression of several genes in dopaminergic midbrain neurons. The externalizing PGS was also significantly associated with aggression scores in the ABCD cohort. Among individuals diagnosed with DBDs in childhood, the absolute risk of later receiving a diagnosis of dissocial personality disorder or emotionally unstable personality disorder was 14.2% in the highest PGS tertile, compared with 6.8% in the lowest PGS tertile. Discussion with 6.8% in the lowest PGS tertile. This preliminary work supports that severe externalizing psychopathology across childhood and adulthood is characterized by substantial shared genetic liability involving brain expressed genes, and in particular genes expressed in dopaminergic neurons. Furthermore, polygenic burden may contribute to the progression from childhood disruptive behaviour disorders to adult antisocial and emotionally unstable psychopathology.