Our program of research has been designed around the premise that breaking the cycle of intergenerational alcoholism could be best achieved by intervening in the lives of high-risk children before alcohol abuse becomes entrenched in their life-styles. To accomplish this, we need a better understanding of how to identify those children at highest risk and the predictors of adverse outcome in these special populations. In 1991 we initiated a study of 8-18 year old high (HR) and low- risk (LR) offspring. The high-risk children/adolescents were from families that were multigenerational for alcoholism affectation (ascertained in a previous award [1984-1990]). These multiplex families had been identified through a pair of alcoholic brothers (child's father and uncle who led us to the full pedigree. Analysis of data from that follow-up (7.5 waves) has provided a number of insights for better understanding the risk factors associated with substance dependence in multigenerational families. HR children have a significantly earlier onset to begin drinking, experience significantly elevated rates of child and adolescent psychopathology, and show evidence of neurodevelopmental delay in achieving age-appropriate levels of P300 amplitude and postural control. Neuroimaging has revealed a lateralized reduction in amygdala volume in HR offspring. Lateralized increases in tissue volume occur during adolescence in limbic areas including the amygdala. Our amygdala results may also point to a neurodevelopmental delay in HR offspring. These markers will ultimately be related to outcome. Our Young Adult follow-up already indicates greatly elevated alcohol dependence in the HR group. The proposed work would include: (1) an 8-18 year old replication sample (N=150) of younger siblings and (2) would extend the Young Adult follow-up to include 361 individuals (many were seen in the child/adolescent follow-up). Consequently, a large number of sibling pairs can be studied using familial resemblance techniques. The existence of a new cohort that includes younger children than are currently being followed would enable us to conduct a longitudinal neuroimaging/P300 study in children before significant drinking has begun and relate this to the expected P300 developmental changes. The replication would include measures previously used in the first 8-18 year old follow-up thus allowing confirmation of our neurodevelopmental delay hypothesis. New measures will be added to explore non-shared environmental effects in these families where sibling pairs are available for study (N=346 sib pairs).

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA005909-18A1
Application #
6430765
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Witt, Ellen
Project Start
1984-01-01
Project End
2007-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
18
Fiscal Year
2002
Total Cost
$943,589
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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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