Dorsal striatal phosphodiesterase 10A and compulsive ethanol use

摘要 酒精使用障碍（AUD）是一种慢性、复发性疾病，29%的美国人在一生中受到折磨1，2， 正在使人丧失能力并增加死亡率。需要新的药物靶点和对AUD的神经生物学见解。 在初步数据的指导下，这份行政补充文件试图扩大对基因变异的研究， 磷酸二酯酶10A（PDE 10A）在英国生物库中进行（和相关的磷酸二酯酶，腺苷酸 调节酒精相关cAMP级联的环化酶和蛋白激酶A相关蛋白）的研究。 种族和社会经济多样的All of Us数据集。特别地，Aim 1将使用两种基因型阵列 和全基因组序列数据集，以确定与问题相关的PDE 10A基因变异， 酒精使用，根据AUDIT-C评分和酒精使用相关诊断及其表达定义 以及与精神病和肥胖相关疾病的遗传相关性。这一行政 补充将增加父母补助金的影响，以确定PDE 10A和其他新的基因变异 cAMP-级联调节基因用于重新利用新型可翻译PDE抑制剂治疗AUD。的 补充将增加遗传发现的敏感性和普遍性，以反映年龄，种族， 美国人口的社会经济多样性。将我们的分析扩展到All of Us数据集迫在眉睫 鉴于已知的不公平的社会健康决定因素与遗传因素相互作用，在酒精方面的作用， 美国境内的相关发病率和合并症。

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.