Browsing by Author "Hesselbrock, Victor"
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Item A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53(Springer Nature, 2013) Wang, Jen-Chyong; Foroud, Tatiana; Hinrichs, Anthony L.; Le, Nhung X. H.; Bertelsen, Sarah; Budde, John P.; Harari, Oscar; Koller, Daniel L.; Wetherill, Leah; Agrawal, Arpana; Almasy, Laura; Brooks, Andrew I.; Bucholz, Kathleen; Dick, Danielle; Hesselbrock, Victor; Johnson, Eric O.; Kang, Sun; Kapoor, Manav; Kramer, John; Kuperman, Samuel; Madden, Pamela A. F.; Manz, Niklas; Martin, Nicholas G.; McClintick, Jeanette N.; Montgomery, Grant W.; Nurnberger, John I., Jr.; Rangaswamy, Madhavi; Rice, John; Schuckit, Marc; Tischfield, Jay A.; Whitfield, John B.; Xuei, Xiaoling; Porjesz, Bernice; Heath, Andrew C.; Edenberg, Howard J.; Bierut, Laura J.; Goate, Alison M.; Medical and Molecular Genetics, School of MedicineSeveral studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.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 Alcohol Use Disorder, Psychiatric Comorbidities, Marriage and Divorce in a High-risk Sample(American Psychological Association, 2022) Thomas, Nathaniel S.; Kuo, Sally I-Chun; Aliev, Fazil; McCutcheon, Vivia V.; Meyers, Jacquelyn M.; Chan, Grace; Hesselbrock, Victor; Kamarajan, Chella; Kinreich, Sivan; Kramer, John R.; Kuperman, Samuel; Lai, Dongbing; Plawecki, Martin H.; Porjesz, Bernice; Schuckit, Marc A.; Dick, Danielle M.; Bucholz, Kathleen K.; Salvatore, Jessica E.; Psychiatry, School of MedicineObjective: To examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample. Method: Participants included European ancestry (EA; n = 4,045) and African ancestry (AA; n = 1,550) individuals from the multigenerational Collaborative Study on the Genetics of Alcoholism (COGA) sample (56% female, Mage ∼ 41 years). Outcomes were lifetime marriage and divorce. Predictors included lifetime AUD, an alcohol problems polygenic score (PRS), and AUD comorbidities, including conduct or antisocial personality disorder (ASP), cannabis dependence/abuse (CAN), frequent tobacco use (TOB), and major depressive disorder (MDD). Mixed effect Cox models and generalized linear mixed effects models were fit. Results: Among EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, ps < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, ps < 0.05) and those with MDD were more likely to marry (HR = 1.34, ps < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, ps < 0.01). Among AA participants, no predictors were significantly associated with divorce. Significant random effects indicated genetic and environmental influences on marriage, but only environmental factors on divorce. Conclusions: In a high-risk sample, AUD was associated with reduced likelihood of marriage in EA and AA individuals and increased risk of divorce in EA individuals. These associations were largely independent of comorbidities. Genetic and environmental background factors contributed to marriage, while only environmental background factors contributed to divorce.Item Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism(Springer Nature, 2019-02-14) Kapoor, Manav; Wang, Jen-Chyong; Farris, Sean P.; Liu, Yunlong; McClintick, Jeanette; Gupta, Ishaan; Meyers, Jacquelyn L.; Bertelsen, Sarah; Chao, Michael; Nurnberger, John; Tischfield, Jay; Harari, Oscar; Zeran, Li; Hesselbrock, Victor; Bauer, Lance; Raj, Towfique; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Edenberg, Howard J.; Mayfield, R. Dayne; Goate, Alison; Medical and Molecular Genetics, School of MedicineAlcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank's alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.Item Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood(MDPI, 2019-10-17) Meyers, Jacquelyn L.; Chorlian, David B.; Johnson, Emma C.; Pandey, Ashwini K.; Kamarajan, Chella; Salvatore, Jessica E.; Aliev, Fazil; Subbie-Saenz de Viteri, Stacey; Zhang, Jian; Chao, Michael; Kapoor, Manav; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John; Tischfield, Jay; Goate, Alison; Foroud, Tatiana; Dick, Danielle M.; Edenberg, Howard J.; Agrawal, Arpana; Porjesz, Bernice; Medical and Molecular Genetics, School of MedicineDifferences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18-31 (beta coefficients ranged from 0.02-0.06, p-values ranged from 10-6-10-12), but not in females. Individuals with higher AD PRS also demonstrated more performance deficits on neuropsychological tasks (Tower of London task, visual span test) as well as increased risk for lifetime DSM-5 alcohol and opioid use disorders. We conclude that measures of neural connectivity, together with neurocognitive performance and substance use behavior, can be used to further understanding of how genetic risk variants from large GWAS of AUD may influence brain function. In addition, these data indicate the importance of examining sex and developmental effects, which otherwise may be masked. Understanding of neural mechanisms linking genetic variants emerging from GWAS to risk for AUD throughout development may help to identify specific points when neurocognitive prevention and intervention efforts may be most effective.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 Associations between Suicidal Thoughts and Behaviors and Genetic Liability for Cognitive Performance, Depression, and Risk-Taking in a High-Risk Sample(Karger, 2021) Johnson, Emma C.; Aliev, Fazil; Meyers, Jacquelyn L.; Salvatore, Jessica E.; Tillman, Rebecca; Chang, Yoonhoo; Docherty, Anna R.; Bogdan, Ryan; Acion, Laura; Chan, Grace; Chorlian, David B.; Kamarajan, Chella; Kuperman, Samuel; Pandey, Ashwini; Plawecki, Martin H.; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J.; Bucholz, Kathleen K.; Nurnberger, John I.; Porjesz, Bernice; Hesselbrock, Victor; Dick, Danielle M.; Kramer, John R.; Agrawal, Arpana; Psychiatry, School of MedicineBackground: Suicidal thoughts and behaviors (STBs) and nonsuicidal self-injury (NSSI) behaviors are moderately heritable and may reflect an underlying predisposition to depression, impulsivity, and cognitive vulnerabilities to varying degrees. Objectives: We aimed to estimate the degrees of association between genetic liability to depression, impulsivity, and cognitive performance and STBs and NSSI in a high-risk sample. Methods: We used data on 7,482 individuals of European ancestry and 3,359 individuals of African ancestry from the Collaborative Study on the Genetics of Alcoholism to examine the links between polygenic scores (PGSs) for depression, impulsivity/risk-taking, and cognitive performance with 3 self-reported indices of STBs (suicidal ideation, persistent suicidal ideation defined as ideation occurring on at least 7 consecutive days, and suicide attempt) and with NSSI. Results: The PGS for depression was significantly associated with all 4 primary self-harm measures, explaining 0.6-2.5% of the variance. The PGS for risk-taking behaviors was also associated with all 4 self-harm behaviors in baseline models, but was no longer associated after controlling for a lifetime measure of DSM-IV alcohol dependence and abuse symptom counts. Polygenic predisposition for cognitive performance was negatively associated with suicide attempts (q = 3.8e-4) but was not significantly associated with suicidal ideation nor NSSI. We did not find any significant associations in the African ancestry subset, likely due to smaller sample sizes. Conclusions: Our results encourage the study of STB as transdiagnostic outcomes that show genetic overlap with a range of risk factors.Item Associations of parent–adolescent closeness with P3 amplitude, frontal theta, and binge drinking among offspring with high risk for alcohol use disorder(Wiley, 2023) Pandey, Gayathri; Kuo, Sally I-Chun; Horne-Osipenko, Kristina A.; Pandey, Ashwini K.; Kamarajan, Chella; Saenz de Viteri, Stacey; Kinreich, Sivan; Chorlian, David B.; Kuang, Weipeng; Stephenson, Mallory; Kramer, John; Anokhin, Andrey; Zang, Yong; Kuperman, Samuel; Hesselbrock, Victor; Schuckit, Marc; Dick, Danielle; Chan, Grace; McCutcheon, Vivia V.; Edenberg, Howard; Bucholz, Kathleen K.; Meyers, Jacquelyn L.; Porjesz, Bernice; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground: Parents impact their offspring's brain development, neurocognitive function, risk, and resilience for alcohol use disorder (AUD) via both genetic and socio-environmental factors. Individuals with AUD and their unaffected children manifest low parietal P3 amplitude and low frontal theta (FT) power, reflecting heritable neurocognitive deficits associated with AUD. Likewise, children who experience poor parenting tend to have atypical brain development and greater rates of alcohol problems. Conversely, positive parenting can be protective and critical for normative development of self-regulation, neurocognitive functioning and the neurobiological systems subserving them. Yet, the role of positive parenting in resiliency toward AUD is understudied and its association with neurocognitive functioning and behavioral vulnerability to AUD among high-risk offspring is less known. Using data from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1256, mean age [SD] = 19.25 [1.88]), we investigated the associations of closeness with mother and father during adolescence with offspring P3 amplitude, FT power, and binge drinking among high-risk offspring. Methods: Self-reported closeness with mother and father between ages 12 and 17 and binge drinking were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. P3 amplitude and FT power were assessed in response to target stimuli using a Visual Oddball Task. Results: Multivariate multiple regression analyses showed that closeness with father was associated with larger P3 amplitude (p = 0.002) and higher FT power (p = 0.01). Closeness with mother was associated with less binge drinking (p = 0.003). Among male offspring, closeness with father was associated with larger P3 amplitude, but among female offspring, closeness with mother was associated with less binge drinking. These associations remained statistically significant with father's and mothers' AUD symptoms, socioeconomic status, and offspring impulsivity in the model. Conclusions: Among high-risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences.Item A Brief Critique of the TATES Procedure(Springer, 2018-03) Aliev, Fazil; Salvatore, Jessica E.; Agrawal, Arpana; Almasy, Laura; Chan, Grace; Edenberg, Howard J.; Hesselbrock, Victor; Kuperman, Samuel; Meyers, Jacquelyn; Dick, Danielle M.; Biochemistry and Molecular Biology, School of MedicineThe Trait-based test that uses the Extended Simes procedure (TATES) was developed as a method for conducting multivariate GWAS for correlated phenotypes whose underlying genetic architecture is complex. In this paper, we provide a brief methodological critique of the TATES method using simulated examples and a mathematical proof. Our simulated examples using correlated phenotypes show that the Type I error rate is higher than expected, and that more TATES p values fall outside of the confidence interval relative to expectation. Thus the method may result in systematic inflation when used with correlated phenotypes. In a mathematical proof we further demonstrate that the distribution of TATES p values deviates from expectation in a manner indicative of inflation. Our findings indicate the need for caution when using TATES for multivariate GWAS of correlated phenotypes.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.