This is a competitive renewal designed to provide a better understanding of the neurobiological determinants of increased risk for alcohol dependence (AD) and other substance use disorders (SUD) in offspring of AD women. This application is enriched by a longitudinal resource that includes a median 10 year follow up of offspring from high risk (HR) multiplex alcohol dependence families and low risk (LR) families. A total of 1167 day long clinical evaluations, measures of environmental variation, ERP recordings to identify P300 amplitude have been performed that spans childhood, adolescence and young adulthood. The initial two awards recruited and characterized women from multiplex AD families, their siblings and parents. Subsequently, offspring of these women were followed prospectively along with census matched control children with data obtained at yearly intervals covering multiple domains of inquiry. During the last award, we identified factors influencing the presence and age of onset for childhood psychopathology and the onset to begin regular drinking. We propose a multivariate approach for understanding how brain morphology and functioning in HR offspring impacts their tendency for emotional dysregulation, behavioral disinhibition, and greater SUD. Alterations in brain systems involved in cognition, emotion and altered sensitivity to acquired reinforcers (rewards) are prominent in long term alcoholics. The limbic aspects of this circuitry include the orbitofrontal cortex and amygdala. Changes in this circuitry associated with behavioral disinhibition can be informative regarding AD etiology. Familial risk group differences in OFC and amygdala volume and connectivity (diffusion tensor imaging [DTI]) will be studied in HR and LR offspring and related to multiple behavioral measures of disinhibition (Aim 1).
Aim 2 will study prenatal environmental exposures (E) that may produce structural alterations in these key components of brain networks designed for emotional and cognitive regulation and reward. The potential G X E interaction of familial/genetic loading (G) with this exposure will be tested for its effect on these structures.
Aim 3 will determin if trajectories of P300 amplitude, an indicator of behavioral disinhibition, are related to OFC brain morphology and SUD. Using prospectively collected data, Aim 4 will examine the effects of postnatal stressors on brain morphology, and as an exploratory focus, test for potential G X E interactions using specific gene variants. Continued follow-up of these offspring to determine SUD outcome in young adulthood can: (1) provide significant clues about the neurobiological underpinnings of multigenerational AD, (2) suggest G X E interactions influencing neurobiological variation, and (3) allow our prospective childhood/adolescent antecedent data to payoff. Importantly, studying the genetic and environmental determinants of brain morphology involved in SUD has the potential for identifying offspring at highest risk for possible intervention and prevention of SUD.

Public Health Relevance

This is a competitive renewal of a program of research designed to provide a better understanding of the neurobiological determinants and consequences of alcohol dependence (AD) in women from families with multiple cases of AD and their offspring. Currently, there is no way to identify which offspring will survive or succumb to AD or related substance use disorders. This study would provide continued young adult follow up to determine offspring SUD outcome, measure brain regions thought to be involved in SUD in these offspring and controls, relate the brain morphology to familial loading for AD and environmental exposures including prenatal exposure to alcohol, thereby providing important clues concerning the neurobiological underpinnings for multigenerational AD and suggest possible interventions.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chiapella, Page
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University of Pittsburgh
Schools of Medicine
United States
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Sharma, Vinod K; Hill, Shirley Y (2017) Differentiating the Effects of Familial Risk for Alcohol Dependence and Prenatal Exposure to Alcohol on Offspring Brain Morphology. Alcohol Clin Exp Res 41:312-322
O'Brien, Jessica W; Hill, Shirley Y (2017) Neural predictors of substance use disorders in Young adulthood. Psychiatry Res Neuroimaging 268:22-26
Hill, Shirley Y; Rompala, Gregory; Homanics, Gregg E et al. (2017) Cross-generational effects of alcohol dependence in humans on HRAS and TP53 methylation in offspring. Epigenomics 9:1189-1203
Hill, Shirley Y; Lichenstein, Sarah D; Wang, Shuhui et al. (2016) Volumetric Differences in Cerebellar Lobes in Individuals from Multiplex Alcohol Dependence Families and Controls: Their Relationship to Externalizing and Internalizing Disorders and Working Memory. Cerebellum 15:744-754
Hill, Shirley Y; Sharma, Vinod; Jones, Bobby L (2016) Lifetime use of cannabis from longitudinal assessments, cannabinoid receptor (CNR1) variation, and reduced volume of the right anterior cingulate. Psychiatry Res Neuroimaging 255:24-34
Hill, Shirley Y; Jones, Bobby L; Steinhauer, Stuart R et al. (2016) Longitudinal predictors of cannabis use and dependence in offspring from families at ultra high risk for alcohol dependence and in control families. Am J Med Genet B Neuropsychiatr Genet 171B:383-95
Hill, Shirley Y; Jones, Bobby L; Zezza, Nicholas et al. (2015) ACN9 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families. Am J Med Genet B Neuropsychiatr Genet 168B:179-87
Hill, Shirley Y; O'Brien, Jessica (2015) Psychological and Neurobiological Precursors of Alcohol Use Disorders in High Risk Youth. Curr Addict Rep 2:104-113
O'Brien, Jessica W; Hill, Shirley Y (2014) Effects of prenatal alcohol and cigarette exposure on offspring substance use in multiplex, alcohol-dependent families. Alcohol Clin Exp Res 38:2952-61
O'Brien, Jessica W; Lichenstein, Sarah D; Hill, Shirley Y (2014) Maladaptive decision making and substance use outcomes in high-risk individuals: preliminary evidence for the role of 5-HTTLPR variation. J Stud Alcohol Drugs 75:643-52

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