This is a revised proposal that aims to identify susceptibility genes in four genomic regions (1p31.0, 6p25.1, 7p22.3, and 17pll.2) previously identified in a genome-wide linkage analysis of two adult generations from our multiplex alcoholism families. This analysis used a Feighner Criteria and DSM-III based definition of alcoholism, similar to the definition of alcoholism used by the only other existing multiplex alcoholism study (COGA) which used a Feighner Criteria and DSM-IIIR definition, to conduct linkage analyses. Like the COGA data set, we have extensive endophenotypic (e.g., P300) and phenotypic variables collected enabling us to later refine our findings in exploratory analyses involving quantitative phenotypes. The four regions show analytic p values between 0.007 and 0.0006 GHP and SIBPAL analytic strategies. One signal (6p25.1) meets chromosome wide significance at p = 0.05. Simulations providing empirical values for previously reported LODPAL results show a need for adjustment when covariates are used. However, maximal LOD values obtained in our LODPAL analyses show convergence with GHP and SIBPAL results suggesting the importance of follow-up of all four regions. Moreover, three of the regions are within 13 Mb of COGA reported signals. Finer mapping of the four regions would include linkage analyses using STRs placed at 5cM and IcM, followed by the use of association-based methods in our family sample, and concluded by confirmation with a case/control design. An efficient SNP genotyping/analysis plan using tag SNP methodologies is proposed for the Linkage disequilibrium (LD) mapping. An attractive feature of our data set is availability of third generation 8-18 year olds for whom extensive phenotypic data are available which would allow for extension of the linkage analyses.
The second aim of our study is complete initial mapping of the third generation for whom DNA is already collected and phenotypic assessment has been done. In order to follow-up on previous linkage results, genotyping data for STRs placed at approximately 9.4 cm intervals for all three generations would be combined and linkage analyses performed using the well validated alcoholism phenotype and the well validated childhood diagnoses obtained from the K-SADS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015168-02
Application #
7071860
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Ren, Zhaoxia
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$592,495
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
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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