Browsing by Author "Nurnberger Jr., John I."

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    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 Medicine
    Alcohol 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.
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    Development of Alcohol Use Disorder as a Function of Age, Severity, and Comorbidity with Externalizing and Internalizing Disorders in a Young Adult Cohort
    (Hapres Limited, 2019) Nurnberger Jr., John I.; Yang, Ziyi; Zang, Yong; Acion, Laura; Bierut, Laura; Bucholz, Kathleen; Chan, Grace; Dick, Danielle M.; Edenberg, Howard J.; Kramer, John; Kuperman, Samuel; Rice, John P.; Schuckit, Marc; Psychiatry, School of Medicine
    Background: As part of the ongoing Collaborative Study of the Genetics of Alcoholism, we performed a longitudinal study of a high risk cohort of adolescents/young adults from families with a proband with an alcohol use disorder, along with a comparison group of age-matched controls. The intent was to compare the development of alcohol problems in subjects at risk with and without comorbid externalizing and internalizing psychiatric disorders. Methods: Subjects (N = 3286) were assessed with a structured psychiatric interview at 2 year intervals over 10 years (2004–2017). The age range at baseline was 12–21. Results: Subjects with externalizing disorders (with or without accompanying internalizing disorders) were at increased risk for the onset of an alcohol use disorder during the observation period. Subjects with internalizing disorders were at greater risk than those without comorbid disorders for onset of a moderate or severe alcohol use disorder. The statistical effect of comorbid disorders was greater in subjects with more severe alcohol use disorders. The developmental trajectory of drinking milestones and alcohol use disorders was also accelerated in those with more severe disorders. Conclusions: These results may be useful for counseling of subjects at risk who present for clinical care, especially those subjects manifesting externalizing and internalizing disorders in the context of a positive family history of an alcohol use disorder. We confirm and extend findings that drinking problems in subjects at greatest risk will begin in early adolescence.
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    Gender-specific gene-environment interaction in alcohol dependence: the impact of daily life events and GABRA2
    (Springer, 2013-09) Perry, Brea L.; Pescosolido, Bernice A.; Bucholz, Kathleen; Edenberg, Howard; Kramer, John; Kuperman, Samuel; Schuckit, Marc Alan; Nurnberger Jr., John I.; Department of Biochemistry and Molecular Biology, IU School of Medicine
    Gender-moderated gene-environment interactions are rarely explored, raising concerns about inaccurate specification of etiological models and inferential errors. The current study examined the influence of gender, negative and positive daily life events, and GABRA2 genotype (SNP rs279871) on alcohol dependence, testing two- and three-way interactions between these variables using multi-level regression models fit to data from 2,281 White participants in the Collaborative Study on the Genetics of Alcoholism. Significant direct effects of variables of interest were identified, as well as gender-specific moderation of genetic risk on this SNP by social experiences. Higher levels of positive life events were protective for men with the high-risk genotype, but not among men with the low-risk genotype or women, regardless of genotype. Our findings support the disinhibition theory of alcohol dependence, suggesting that gender differences in social norms, constraints and opportunities, and behavioral undercontrol may explain men and women's distinct patterns of association.