Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia

There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity.

We tested the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: the Collaborative Genetic Study of Nicotine Dependence (ascertained for tobacco use disorder; n = 918 cases; 988 control subjects), the Collaborative Study on the Genetics of Alcoholism (ascertained for alcohol use disorder; n = 643 cases; 384 control subjects), and the Family Study of Cocaine Dependence (ascertained for cocaine use disorder; n = 210 cases; 317 control subjects). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to the 1000 Genomes reference panel.

In each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo-R² range 0.8-3.7%; minimum p = 4 × 10^-23).

These results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.