Dorsal striatal phosphodiesterase 10A and compulsive ethanol use

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ABSTRACT Alcohol use disorder (AUD) is a chronic, relapsing disorder that afflicts 29% of Americans in their lifetime1,2, is disabling2 and increases mortality3. New drug targets and neurobiological insight for AUD are needed. Guided by preliminary data, this administrative supplement seeks to expand studies of gene variants in phosphodiesterase 10A (PDE10A) performed in the UK Biobank (and related phosphodiesterases, adenylyl cyclases and protein kinase A-related proteins that regulate alcohol-related cAMP cascades) to studies in the ethincally and socioeconomically diverse All of Us dataset. Specially, Aim 1 will use both genotyped arrays and whole genome sequence datasets to identify PDE10A gene variants that associate with problematic alcohol use, as defined by AUDIT-C scores and alcohol use-associated diagnoses, as well as their expression and genetic correlation to often comorbid psychiatric and obesity-related diagnoses. This administrative supplement will increase the impact of the parent grant to identify novel gene variants in PDE10A and other cAMP-cascade regulating genes towards repurposing novel translatable PDE inhibitors to treat AUD. The supplement will increase the sensitivity and generalizability of genetic discovery to reflect the age, ethnic, and socioeconomic diversity of the American population. Extending our analyses to the All of Us dataset is pressing given the known role of inequitable social determinants of health, interacting with genetic factors, in alcohol- related morbidity and comorbidity within the United States.