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Genetic landscape of substance use and psychopathology
Family and gene-mapping studies have revealed that behavioral phenotypes are heritable, genetically correlated, and influenced by a large number of genetic variants each having small effect size. Despite this, the potential variability in heritability, genetic correlation, polygenicity, and the natural selection signals across a wide spectrum of behavioral domains has not been fully characterized. I will present a program of research meant to understand and characterize specific genetic risk loci associated with psychopathology, as well as the genetic architecture and structure, of psychopathology. We conducted a genome-wide association study (GWAS) meta-analysis of nicotine and alcohol use in up to 1.2 million individuals, discovering >400 genomic locations robustly associated with these addictive behaviors. We then jointly analyzed these results with summary statistics from well-powered GWAS (N ranging from 50,000 to 1.2 million) for 12* phenotypes related to psychopathology including risk-taking, major depressive disorder, neuroticism, schizophrenia, bipolar disorder, and cognitive ability. We discovered >300 genomic locations that showed evidence of pleiotropy with 2 or more phenotypes, and will present for discussion highly pleiotropic locations with biologically plausible risk genes for these conditions. We also evaluated heritability and genetic correlations among these phenotypes using genome-wide techniques (e.g., LD Score Regression), which resulted in a factor structure similar to that observed for phenotypic correlation matrices of these conditions, consistent with recent continuum conceptualizations of mental illness. The results are an important first step in characterizing the pleiotropic nature of genetic risk for mental illness at not only the genome-wide level, but also for individual genomic loci and specific genes.
*The list will be significantly expanded by the September meeting in Buffalo.