Evidence of shared genetic influences underlying schizophrenia and alcohol use disorder, but not alcohol consumption

Abstract

AbstractBackgroundAlcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and recent genome-wide association studies (GWAS) have identified significant genetic correlations between them. In parallel, mounting evidence from GWAS suggests that alcohol consumption is only weakly genetically correlated with SCZ, but this has not yet been systematically investigated.MethodsWe used the largest published GWAS for AUD (total cases = 77,822) and SCZ (total cases = 46,827) to systematically identify genetic variants that influence both disorders (in either the same or opposite direction of effect) as well as disorder-specific loci, and contrast our findings with GWAS data for drinks per week (DPW; N = 537,349) as a measure of alcohol consumption.ResultsWe identified 55 independent genome-wide significant SNPs with the same direction of effect on AUD and SCZ, 9 with robust opposite effects, and 99 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). The genetic correlation between DPW and SCZ (rg = 0.102, SE = 0.022) was significantly lower than that for AUD and SCZ (rg = 0.392, SE = 0.029; p-value of the difference = 9.3e-18), and the genetic covariance between DPW and SCZ was not enriched for any meaningful tissue-specific categories.ConclusionsOur findings provide a detailed view of genetic loci that influence risk of both AUD and SCZ, suggest that biological commonalities underlying genetic variants with an effect on both disorders are manifested in brain tissues, and provide further evidence that SCZ shares meaningful genetic overlap with AUD and not merely alcohol consumption.