Concurrent substance use and psychiatric disorders: a pipeline to investigate shared genomic liability and causal effects

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Project Summary Substance use and other psychiatric disorders result in enormous personal, healthcare, and economic costs. Substance use (e.g., tobacco use disorder) and psychiatric (e.g., schizophrenia) disorders are highly comorbid. Three main theories have been proposed to explain the high comorbidity of tobacco use and schizophrenia: 1) self-medication (e.g., schizophrenia promotes tobacco use due to nicotine’s effect on reducing cognitive deficits and medication side effects), 2) tobacco use causes schizophrenia, and 3) a shared liability, due to shared genetic and environmental factors. Tobacco use and schizophrenia are each highly heritable (~60- 80%) and we and others have shown that they share several common genetic risk factors. Two traits may share genetic risk factors due pleiotropy (i.e., a gene variant influences both traits) or because one disorder causes the other. Furthermore, shared genetic risk may be present in all individuals (i.e., whole-group pleiotropy) or may be restricted to a subset of individuals (i.e., sub-group heterogeneity). Using our expertise in tobacco use, biomarkers, schizophrenia, statistical genetics, and transcriptional analyses, we will develop a comprehensive analytic pipeline to elucidate the shared genomic liability of tobacco use and schizophrenia, and identify potential causal effects. Our study improves upon initial cross-disorder analyses, and involves 1) obtaining data from the largest available genomics datasets of schizophrenia and tobacco use, 2) examining genetic correlation between the traits, 3) identifying shared genetic variants, 4) examining biological (i.e., mechanistic) pathways, 5) exploring functional effects of the shared genetic variants, and 6) testing causal directions and effects of whole-group pleiotropy versus sub-group heterogeneity. In Aim 1, we will become proficient in all 6 steps of the analytic pipeline by analyzing women and men together. In Aim 2, we will conduct genome-wide sex-based analyses of tobacco use to determine the feasibility of using sex-based genomic analyses in future investigations of concurrent psychiatric disorders. To develop the pipeline, we will use nicotine intake biomarkers, which capture tobacco use more accurately than self-reported measures. However, GWAS of self-reported traits or diagnostic criteria could be used when biomarkers are unavailable. This grant will train the young investigator PI for a larger genomics program investigating the shared genomic liability and causality between other pairs of heritable and concurrent psychiatric disorders. We will apply this pipeline to diverse populations as the datasets become available. Through these efforts, we will better understand the biological vulnerability to developing co-occurring substance use and psychiatric disorders. This work may lead to improved prevention and treatment approaches, as well as reveal novel targets for drug discovery.