Are shared genetic effects between schizophrenia and substance abuse mediated by genetic effects on brain structure phenotypes? A multiplex extended pedigree study

Individuals with schizophrenia are at greatly increased risk for substance abuse and yet the reasons for this comorbidity have not been fully explained. One potential explanation for this relationship could be that there are genetic effects that jointly increase risk for both schizophrenia and substance abuse (e.g., pleiotropy). Using a multiplex, extended pedigree study design (N=1306), the current project sought to determine the degree to which genetic effects are shared between schizophrenia and four substance use diagnoses (Aim 1a): a broad measure of any substance abuse/dependence; alcohol abuse/dependence; cannabis abuse/dependence; and regular smoking (nicotine). We also assessed the specificity of the genetic relationship between schizophrenia and substance abuse by using depression as a diagnostic control (Aim 1b). Consistent with our predictions, we found that schizophrenia was moderately and significantly genetically correlated with any substance abuse/dependence (Rg = 0.27, p = 0.033), alcohol abuse/dependence (Rg = 0.35, p = 0.006), and cannabis abuse/dependence (Rg = 0.24, p = 0.011), and that this genetic relationship was specific to substance abuse (depression: Rg = -0.27, p = 0.500). Next, we assessed shared genetic effects between 44 brain structure phenotypes and schizophrenia (Aim 2a), substance abuse (Aim 2b), and depression (Aim 2c) using a subset of the sample that underwent structural magnetic resonance imaging (N=506). We found that the genetic effects on hippocampal volume were significantly genetically correlated with both schizophrenia (Rg = -0.53, p = 0.001) and substance abuse (Rg = -0.57, p = 0.043), and that brain structures genetically associated with schizophrenia were not genetically associated with depression. Using a novel analytic approach, we found that the shared genetic effects between schizophrenia and substance abuse were mediated by the genetic effects on hippocampal volume, indicating that there is substantial shared genetic variation among all three phenotypes. These findings provide valuable support for the theory of shared genetic effects playing a substantial role in the high comorbidity between schizophrenia and substance abuse and identify the unique role of hippocampus in the pathophysiology of both schizophrenia and substance abuse.