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Browsing by Author "Hesselbrock, Michie"
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Item Association of substance dependence phenotypes in the COGA sample(Wiley, 2015-05) Wetherill, Leah; Agrawal, Arpana; Kapoor, Manav; Bertelsen, Sarah; Bierut, Laura J.; Brooks, Andrew; Dick, Danielle; Hesselbrock, Michie; Hesselbrock, Victor; Koller, Daniel L.; Le, Nhung; Nurnberger Jr., John I.; Salvatore, Jessica E.; Schuckit, Marc; Tischfield, Jay A.; Wang, Jen-Chyong; Xuei, Xiaoling; Edenberg, Howard J.; Porjesz, Bernice; Bucholz, Kathleen; Goate, Alison M.; Foroud, Tatiana; Department of Medical & Molecular Genetics, IU School of MedicineAlcohol and drug use disorders are individually heritable (50%). Twin studies indicate that alcohol and substance use disorders share common genetic influences, and therefore may represent a more heritable form of addiction and thus be more powerful for genetic studies. This study utilized data from 2322 subjects from 118 European-American families in the Collaborative Study on the Genetics of Alcoholism sample to conduct genome-wide association analysis of a binary and a continuous index of general substance dependence liability. The binary phenotype (ANYDEP) was based on meeting lifetime criteria for any DSM-IV dependence on alcohol, cannabis, cocaine or opioids. The quantitative trait (QUANTDEP) was constructed from factor analysis based on endorsement across the seven DSM-IV criteria for each of the four substances. Heritability was estimated to be 54% for ANYDEP and 86% for QUANTDEP. One single-nucleotide polymorphism (SNP), rs2952621 in the uncharacterized gene LOC151121 on chromosome 2, was associated with ANYDEP (P = 1.8 × 10(-8) ), with support from surrounding imputed SNPs and replication in an independent sample [Study of Addiction: Genetics and Environment (SAGE); P = 0.02]. One SNP, rs2567261 in ARHGAP28 (Rho GTPase-activating protein 28), was associated with QUANTDEP (P = 3.8 × 10(-8) ), and supported by imputed SNPs in the region, but did not replicate in an independent sample (SAGE; P = 0.29). The results of this study provide evidence that there are common variants that contribute to the risk for a general liability to substance dependence.Item Familial association of abstinent remission from alcohol use disorder in first-degree relatives of alcohol-dependent treatment-seeking probands(Wiley, 2017) McCutcheon, Vivia V.; Schuckit, Marc A.; Kramer, John R.; Chan, Grace; Edenberg, Howard J.; Smith, Tom L.; Bender, Annah K.; Hesselbrock, Victor; Hesselbrock, Michie; Bucholz, Kathleen K.; Department of Biochemistry & Molecular Biology, IU School of MedicineBackground and Aims Studies that have included family history of alcohol use disorder (AUD) as a predictor of remission from AUD have yielded few significant results. The goals of this study were to estimate the association of persistent AUD, non-abstinent remission and abstinent remission (‘AUD/remission status’) in a proband with AUD/remission status in a relative and to test whether this association differed in related and unrelated proband-relative pairs. Design High-risk family study of alcohol dependence. Probands were recruited from treatment settings and relatives were invited to participate. Baseline assessments occurred between 1991 and 1998 with follow-up between 1996 and 2005. Half of probands were matched with a biological 1st-degree relative with life-time AUD (related group) and half of probands were paired with an unrelated individual with life-time AUD (unrelated group). Setting Brooklyn, New York; Indianapolis, Indiana; Iowa City, Iowa; San Diego, California; Farmington, Connecticut; and St Louis, Missouri, USA. Participants A total of 606 probands (25.7% female, mean age 37.7) with baseline and follow-up data and 606 of their 1st-degree relatives who had life-ime AUDs (45.8% female, mean age 36.2 years). Measurements Persistent AUD, non-abstinent remission and abstinent remission were based on self-report interview data on most recent AUD symptoms and alcohol consumption. Dependent variable was relatives’ AUD/remission status. Independent variable was probands’ AUD/remission status. Findings A total of 34.6% of probands and 20.6% of relatives were abstinent and 11.1% of probands and 22.8% of relatives were in non-abstinent remission. AUD/remission status was correlated significantly in related (r = 0.23, P = 0.0037) but not in unrelated pairs. A significant interaction of probands’ abstinent remission with a variable representing related (versus unrelated, P = 0.003) pairs suggested a familial association for abstinent remission. In related pairs, individuals with an abstinent proband were more likely to be abstinent themselves than were individuals whose proband had persistent AUD [relative risk ratio = 3.27, 95% confidence interval (CI) = 1.56–6.85, P = 0.002]; this association was not significant in unrelated pairs. Conclusions The likelihood of abstinent remission among people with alcohol use disorder appears to be more than three times greater for individuals who are related to an abstinent proband versus those related to a proband with persistent alcohol use disorder.Item A GABRA2 Polymorphism Improves a Model for Prediction of Drinking Initiation(Elsevier, 2017-09) Kuperman, Samuel; Chan, Grace; Kramer, John; Wetherill, Leah; Acion, Laura; Edenberg, Howard J.; Foroud, Tatiana M.; Nurnberger, John, Jr.; Agrawal, Arpana; Anokhin, Andrey; Brooks, Andrew; Hesselbrock, Victor; Hesselbrock, Michie; Schuckit, Marc; Tischfield, Jay; Liu, Xiangtao; Department of Biochemistry & Molecular Biology, IU School of MedicineBackground Survival analysis was used to explore the addition of a single nucleotide polymorphism (SNP) and covariates (sex, interview age, and ancestry) on a previously published model's ability to predict onset of drinking. A SNP variant of rs279871, in the chromosome 4 gene encoding gamma-aminobutyric acid receptor (GABRA2), was selected due to its associations with alcoholism in young adults and with behaviors that increased risk for early drinking. Methods A subsample of 674 adolescents (ages 14–17) participating in the Collaborative Study on the Genetics of Alcoholism (COGA) was examined using a previously derived Cox proportional hazards model containing: 1) number of non-drinking related conduct disorder (CD) symptoms, 2) membership in a high-risk alcohol-dependent (AD) family, 3) most best friends drank (MBFD), 4) Achenbach Youth Self Report (YSR) externalizing score, and 5) YSR social problems score. The above covariates along with the SNP variant of GABRA2, rs279871, were added to this model. Five new prototype models were examined. The most parsimonious model was chosen based on likelihood ratio tests and model fit statistics. Results The final model contained four of the five original predictors (YSR social problems score was no longer significant and hence dropped from subsequent models), the three covariates, and a recessive GABRA2 rs279871 TT genotype (two copies of the high-risk allele containing thymine). The model indicated that adolescents with the high-risk TT genotype were more likely to begin drinking than those without this genotype. Conclusions The joint effect of the gene (rs279871 TT genotype) and environment (MBFD) on adolescent alcohol initiation is additive, but not interactive, after controlling for behavior problems (CD and YSR externalizing score). This suggests that the impact of the high-risk TT genotype on the onset of drinking is affected by controlling for peer drinking and does not include genotype-by-environment interactions.