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Association Between Substance Use Disorder And Polygenic Liability To Schizophrenia

By Sarah Hartz, Amy Horton, Mary Oehlert, Caitlin E Carey, Arpana Agrawal, Ryan Bogdan, Li-Shiun Chen, Dana B Hancock, Eric O. Johnson, Carlos Pato, Michele T Pato, John P. Rice, Laura J. Bierut

Posted 21 Apr 2017
bioRxiv DOI: 10.1101/129288 (published DOI: 10.1016/j.biopsych.2017.04.020)

Background: There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity. Methods: Here, we test 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: COGEND (ascertained for nicotine dependence n=918 cases, 988 controls), COGA (ascertained for alcohol dependence n=643 cases, 384 controls), and FSCD (ascertained for cocaine dependence n=210 cases, 317 controls). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to 1000 Genomes reference panel. Results: 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=4x10-23). Conclusions: 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.

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