Shared genetic effects among schizophrenia, substance use disorder, and hippocampal volume in a multiplex extended...

Many individuals with schizophrenia have comorbid substance use disorders (SUD) and yet the reasons for this comorbidity are largely unknown. The current study examined if shared genetic effects jointly increase risk for both schizophrenia and SUD and if shared genetic effects on brain structure phenotypes mediate this relationship.

Data were collected using a multiplex extended pedigree design ascertained through schizophrenia probands (total sample N = 1306, with N = 789 relatives and N = 517 unrelated controls) to investigate the degree to which genetic effects are shared among schizophrenia, four SUDs, and structural MRI measures of surface area, cortical thickness, and subcortical volumes. Given that all predictions were directional (e.g., that schizophrenia would be positively genetically correlated with substance use), one-tailed t-tests were used with false discovery rate (FDR) correction when appropriate.

As predicted, schizophrenia was significantly genetically correlated with any SUD excluding nicotine (R_g = 0.27, p = 0.033), alcohol use disorder (R_g = 0.35, p = 0.006), and cannabis use disorder (R_g = 0.24, p = 0.011). Next, using a subset of the sample that underwent structural magnetic resonance imaging (N = 506), brain structure phenotypes genetically correlated with both schizophrenia and SUD were identified. Only hippocampal volume was significantly genetically correlated with both schizophrenia (R_g = -0.53, p = 0.001) and any SUD (R_g = -0.57, p = 0.043). Furthermore, genetic effects shared between schizophrenia and SUD were significantly statistically mediated by the genetic effects on hippocampal volume.

These findings indicate that shared genetic effects may partially explain the observed comorbidity between schizophrenia and SUD and may suggest a unique role of the hippocampus in the pathophysiology of both schizophrenia and SUD.