Bogdan, R. | bioRxiv Science

bioRxiv2018

Convergent evidence for predispositonal effects of brain volume on alcohol consumption

BackgroundAlcohol use has been reliably associated with smaller subcortical and cortical regional gray matter volumes (GMVs). Whether these associations reflect shared predisposing risk factors and/or causal consequences of alcohol use remains poorly understood.\n\nMethodsData came from 3 neuroimaging samples (total n=2,423), spanning childhood/adolescence to middle age, with prospective or family-based data. First, we identified replicable GMV correlates of alcohol use. Next, we used family-based and longitudinal data to test whether these associations may plausibly reflect a predispositional liability for alcohol use, and/or a causal consequence of alcohol use. Finally, we evaluated whether GWAS-defined genomic risk for alcohol consumption is enriched for genes preferentially expressed in regions identified in our neuroimaging analyses, using heritability and gene-set enrichment, and transcriptome-wide association study (TWAS) approaches.\n\nResultsSmaller right dorsolateral prefrontal cortex (DLPFC; i.e., middle and superior frontal gyri) and insula GMVs were associated with increased alcohol use across samples. Family-based and prospective longitudinal data suggest these associations are genetically conferred and that DLPFC GMV prospectively predicts future use and initiation. Genomic risk for alcohol use was enriched in gene-sets preferentially expressed in the DLPFC and associated with differential expression of C16orf93, CWF19L1, and C18orf8 in the DLPFC.\n\nConclusionsThese data suggest that smaller DLPFC and insula GMV plausibly represent predispositional risk factors for, as opposed to consequences of, alcohol use. Alcohol use, particularly when heavy, may potentiate these predispositional risk factors. DLPFC and insula GMV represent promising biomarkers for alcohol consumption liability and related psychiatric and behavioral phenotypes.

neuroscience↗

bioRxiv2017

Association Between Substance Use Disorder And Polygenic Liability To Schizophrenia

BackgroundThere are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity.\n\nMethodsHere, 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.\n\nResultsIn 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).\n\nConclusionsThese 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.

genetics↗