Browsing by Author "Bucholz, Kathleen"
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Item A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks(Springer, 2013) Kapoor, Manav; Wang, Jen-Chyong; Wetherill, Leah; Le, Nhung; Bertelsen, Sarah; Hinrichs, Anthony L.; Budde, John; Agrawal, Arpana; Bucholz, Kathleen; Dick, Danielle; Harari, Oscar; Hesselbrock, Victor; Kramer, John; Nurnberger, John I., Jr.; Rice, John; Saccone, Nancy; Schuckit, Marc; Tischfield, Jay; Porjesz, Bernice; Edenberg, Howard J.; Bierut, Laura; Foroud, Tatiana; Goate, Alison; Medical and Molecular Genetics, School of MedicineMaximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10(-7)) and PLCL1 genes (p = 4.1 × 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10(-3), 3 × 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.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 Changes over time in endorsement of 11 DSM-IV alcohol use disorder (AUD) criteria in young adults with persistent or recurrent AUD in The Collaborative Study on the Genetics of Alcoholism(Wiley, 2023) Schuckit, Marc A.; Smith, Tom L.; Danko, George; Tear, Jake; Hennies, Jessica; Mendoza, Lee Anne; Hesselbrock, Victor; Edenberg, Howard J.; Hesselbrock, Michie; Bucholz, Kathleen; Chan, Grace; Kuperman, Samuel; Francis, Meredith W.; Plawecki, Martin H.; Biochemistry and Molecular Biology, School of MedicineBackground: Endorsement of specific Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) alcohol use disorder (AUD) criteria have been shown to change significantly over time in men in their thirties who have persistent or recurrent AUD. However, few studies have documented whether the endorsement of AUD items changes over time in younger individuals or in women. We evaluated changes in the endorsement of AUD criteria in 377 men and women with persistent or recurrent AUD during their twenties. Methods: Information on AUD-item endorsement over time was available for 223 men and 154 women aged 20-25 with persistent or recurrent AUD in at least three interviews in the Collaborative Study on the Genetics of Alcoholism. The statistical significance of endorsement changes over time was evaluated using the related-sample Cochran's Q test for the full sample and for men and women separately. Additional analyses evaluated sex differences in the patterns of change. Results: In the full sample, the predominant pattern was for a significant increase in the rates of endorsement for six of the seven alcohol dependence criteria but not in the four abuse criteria. A similar pattern was seen within men, but women had significant changes in only three of the seven dependence criteria. Conclusions: Endorsement of the seven alcohol dependence criteria among individuals with persistent or recurrent AUD in their twenties generally increased, but few changes were observed in the rates of endorsement of the four abuse criteria. These results are discussed in terms of how they reflect on the nature of AUD and the DSM criteria.Item Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts(Springer, 2022-10-04) Barr, Peter B.; Driver, Morgan N.; Kuo, Sally I-Chun; Stephenson, Mallory; Aliev, Fazil; Linnér, Richard Karlsson; Marks, Jesse; Anokhin, Andrey P.; Bucholz, Kathleen; Chan, Grace; Edenberg, Howard J.; Edwards, Alexis C.; Francis, Meredith W.; Hancock, Dana B.; Harden, K. Paige; Kamarajan, Chella; Kaprio, Jaakko; Kinreich, Sivan; Kramer, John R.; Kuperman, Samuel; Latvala, Antti; Meyers, Jacquelyn L.; Palmer, Abraham A.; Plawecki, Martin H.; Porjesz, Bernice; Rose, Richard J.; Schuckit, Marc A.; Salvatore, Jessica E.; Dick , Danielle M.; Medical and Molecular Genetics, School of MedicineSubstance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.Item 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 MedicineBackground: 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.Item Early Sexual Trauma Exposure and Neural Response Inhibition in Adolescence and Young Adults: Trajectories of Frontal Theta Oscillations During a Go/No-Go Task(Elsevier, 2019) Meyers, Jacquelyn; McCutcheon, Vivia V.; Pandey, Ashwini K.; Kamarajan, Chella; Subbie, Stacey; Chorlian, David; Salvatore, Jessica; Pandey, Gayathri; Almasy, Laura; Anokhin, Andrey; Bauer, Lance; Bender, Annah; Dick, Danielle M.; Edenberg, Howard J.; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Agrawal, Arpana; Bucholz, Kathleen; Porjesz, Bernice; Biochemistry and Molecular Biology, School of MedicineObjective Trauma, particularly when experienced early in life, can alter neurophysiologic and behavioral development, thereby increasing risk for substance use disorders and related psychopathology. However, few studies have empirically examined trauma using well-characterized developmental samples that are followed longitudinally. Method The association of assaultive, non-assaultive, and sexual assaultive experiences before 10 years of age with developmental trajectories of brain function during response inhibition was examined by measuring electrophysiologic theta and delta oscillations during no-go and go conditions in an equal probability go/no-go task. Data were drawn from the Collaborative Study of the Genetics of Alcoholism (COGA) prospective cohort, composed of offspring from high-risk and comparison families who were 12 to 22 years old at enrollment, with follow-ups at 2-year intervals since 2004. In addition, other important predictors of neurophysiologic functioning (eg, substance use, impulsivity, and parental alcohol use disorders) were investigated. Moreover, associations of neurophysiologic functioning with alcohol and cannabis use disorder symptom counts and externalizing and internalizing psychopathology were examined. Results Individuals exposed to sexual assaultive trauma before 10 years of age had slower rates of change in developmental trajectories of no-go frontal theta during response inhibition. Importantly, effects remained significant after accounting for exposure to other traumatic exposures, such as parental history of alcohol use disorder and participants’ substance use, but not measures of impulsivity. Further, slower rates of change in no-go frontal theta adolescent and young adult development were associated with increased risk for alcohol use disorder symptoms and internalizing psychopathology, but not for cannabis use disorder symptoms or externalizing psychopathology. Conclusion Childhood sexual assault is associated with atypical frontal neurophysiologic development during response inhibition. This could reflect alterations in frontal lobe development, synaptic pruning, and/or cortical maturation involving neural circuits for inhibitory control. These same areas could be associated with increased risk for young adult alcohol use disorder symptoms and internalizing psychopathology. These findings support the hypothesis that changes in neurocognitive development related to early sexual trauma exposure could increase the risk for mental health and substance use problems in young adulthood.Item Examining Social Genetic Effects on Educational Attainment via Parental Educational Attainment, Income, and Parenting(American Psychological Association, 2022) Su, Jinni; Kuo, Sally I-Chun; Trevino, Angel; Barr, Peter B.; Aliev, Fazil; Bucholz, Kathleen; Chan, Grace; Edenberg, Howard J.; Kuperman, Samuel; Lai, Dongbing; Meyers, Jacquelyn L.; Pandey, Gayathri; Porjesz, Bernice; Dick, Danielle M.; Biochemistry and Molecular Biology, School of MedicineHigher parental educational attainment is associated with higher offspring educational attainment. In this study, we incorporated genotypic and phenotypic information from fathers, mothers, and offspring to disentangle the genetic and socioenvironmental pathways underlying this association. Data were drawn from a sample of individuals of European ancestry from the collaborative study on the genetics of alcoholism (n = 4,089; 51% female). Results from path analysis indicated that paternal and maternal educational attainment genome-wide polygenic scores were associated with offspring educational attainment, above and beyond the effect of offspring education polygenic score. Parental educational attainment, income, and parenting behaviors served as important socioenvironmental pathways that mediated the effect of parental education polygenic score on offspring educational attainment. Our study highlights the importance of using genetically informed family studies to disentangle the genetic and socioenvironmental pathways underlying parental influences on human development.Item Family-based association analysis of alcohol dependence criteria and severity(Wiley Blackwell (Blackwell Publishing), 2014-02) Wetherill, Leah; Kapoor, Manav; Agrawal, Arpana; Bucholz, Kathleen; Koller, Daniel; Bertelsen, Sarah E.; Le, Nhung; Wang, Jen-Chyong; Almasy, Laura; Hesselbrock, Victor; Kramer, John; Nurnberger, John I.; Schuckit, Marc; Tischfield, Jay A.; Xuei, Xiaoling; Porjesz, Bernice; Edenberg, Howard J.; Goate, Alison M.; Foroud, Tatiana; Department of Medical and Molecular Genetics, IU School of MedicineBackground Despite the high heritability of alcohol dependence (AD), the genes found to be associated with it account for only a small proportion of its total variability. The goal of this study was to identify and analyze phenotypes based on homogeneous classes of individuals to increase the power to detect genetic risk factors contributing to the risk of AD. Methods The 7 individual DSM-IV criteria for AD were analyzed using latent class analysis (LCA) to identify classes defined by the pattern of endorsement of the criteria. A genome-wide association study was performed in 118 extended European American families (n = 2,322 individuals) densely affected with AD to identify genes associated with AD, with each of the seven DSM-IV criteria, and with the probability of belonging to two of three latent classes. Results Heritability for DSM-IV AD was 61%, and ranged from 17-60% for the other phenotypes. A SNP in the olfactory receptor OR51L1 was significantly associated (7.3 × 10−8) with the DSM-IV criterion of persistent desire to, or inability to, cut down on drinking. LCA revealed a three-class model: the “low risk” class (50%) rarely endorsed any criteria, and none met criteria for AD; the “moderate risk” class (33) endorsed primarily 4 DSM-IV criteria, and 48% met criteria for AD; the “high risk” class (17%) manifested high endorsement probabilities for most criteria and nearly all (99%) met criteria for AD One single nucleotide polymorphism (SNP) in a sodium leak channel NALCN demonstrated genome-wide significance with the high risk class (p=4.1 × 10−8). Analyses in an independent sample did not replicate these associations. Conclusion We explored the genetic contribution to several phenotypes derived from the DSM-IV alcohol dependence criteria. The strongest evidence of association was with SNPs in NALCN and OR51L1.Item 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 MedicineGender-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.Item Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults(Springer, 2013) Chorlian, David B.; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Dick, Danielle; Almasy, Laura; Bauer, Lance; Bucholz, Kathleen; Foroud, Tatiana; Hesselbrock, Victor; Kang, Sun J.; Kramer, John; Kuperman, Sam; Nurnberger, John, Jr.; Rice, John; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J.; Goate, Alison; Bierut, Laura; Porjesz, Bernice; Medical and Molecular Genetics, School of MedicineDiscrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.