Browsing by Author "Schuckit, Marc"

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    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 Medicine
    Maximum 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.
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    Alcohol Use Disorder Polygenic Score Compared With Family History and ADH1B
    (American Medical Association, 2024-12-02) Lai, Dongbing; Zhang, Michael; Abreu, Marco; Schwantes-An, Tae-Hwi; Chan, Grace; Dick, Danielle M.; Kamarajan, Chella; Kuang, Weipeng; Nurnberger, John I.; Plawecki, Martin H.; Rice, John; Schuckit, Marc; Porjesz, Bernice; Liu, Yunlong; Foroud, Tatiana; Medical and Molecular Genetics, School of Medicine
    Importance: Identification of individuals at high risk of alcohol use disorder (AUD) and subsequent application of prevention and intervention programs has been reported to decrease the incidence of AUD. The polygenic score (PGS), which measures an individual's genetic liability to a disease, can potentially be used to evaluate AUD risk. Objective: To assess the estimability and generalizability of the PGS, compared with family history and ADH1B, in evaluating the risk of AUD among populations of European ancestry. Design, setting, and participants: This genetic association study was conducted between October 1, 2023, and May 21, 2024. A 2-stage design was used. First, the pruning and thresholding method was used to calculate PGSs in the screening stage. Second, the estimability and generalizability of the best PGS was determined using 2 independent samples in the testing stage. Three cohorts ascertained to study AUD were used in the screening stage: the Collaborative Study on the Genetics of Alcoholism (COGA), the Study of Addiction: Genetics and Environment (SAGE), and the Australian Twin-Family Study of Alcohol Use Disorder (OZALC). The All of Us Research Program (AOU), which comprises participants with diverse backgrounds and conditions, and the Indiana Biobank (IB), consisting of Indiana University Health system patients, were used to test the best PGS. For the COGA, SAGE, and OZALC cohorts, cases with AUD were determined using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or Fifth Edition (DSM-5) criteria; controls did not meet any criteria or did not have any other substance use disorders. For the AOU and IB cohorts, cases with AUD were identified using International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, Tenth Revision (ICD-10) codes; controls were aged 21 years or older and did not have AUD. Exposure: The PGS was calculated using single-nucleotide variants with concordant effects in 3 large-scale genome-wide association studies of AUD-related phenotypes. Main outcomes and measures: The main outcome was AUD determined with DSM-IV or DSM-5 criteria and ICD-9 or ICD-10 codes. Generalized linear mixed models and logistic regression models were used to analyze related and unrelated samples, respectively. Results: The COGA, SAGE, and OZALC cohorts included a total of 8799 samples (6323 cases and 2476 controls; 50.6% were men). The AOU cohort had a total of 116 064 samples (5660 cases and 110 404 controls; 60.4% were women). The IB cohort had 6373 samples (936 cases and 5437 controls; 54.9% were women). The 5% of samples with the highest PGS in the AOU and IB cohorts were approximately 2 times more likely to develop AUD (odds ratio [OR], 1.96 [95% CI, 1.78-2.16]; P = 4.10 × 10-43; and OR, 2.07 [95% CI, 1.59-2.71]; P = 9.15 × 10-8, respectively) compared with the remaining 95% of samples; these ORs were comparable to family history of AUD. For the 5% of samples with the lowest PGS in the AOU and IB cohorts, the risk of AUD development was approximately half (OR, 0.53 [95% CI, 0.45-0.62]; P = 6.98 × 10-15; and OR, 0.57 [95% CI, 0.39-0.84]; P = 4.88 × 10-3) compared with the remaining 95% of samples; these ORs were comparable to the protective effect of ADH1B. PGS had similar estimabilities in male and female individuals. Conclusions and relevance: In this study of AUD risk among populations of European ancestry, PGSs were calculated using concordant single-nucleotide variants and the best PGS was tested in targeted datasets. The findings suggest that the PGS may potentially be used to evaluate AUD risk. More datasets with similar AUD prevalence as in general populations are needed to further test the generalizability of PGS.
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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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    Associations between alcohol use disorder polygenic score and remission in participants from high-risk families and the Indiana Biobank
    (Wiley, 2024) Lai, Dongbing; Kuo, Sally I-Chun; Wetherill, Leah; Aliev, Fazil; Zhang, Michael; Marco, Abreu; Schwantes-An, Tae-Hwi; Dick, Danielle; Francis, Meredith W.; Johnson, Emma C.; Kamarajan, Chella; Kinreich, Sivan; Kuperman, Samuel; Meyers, Jacquelyn; Nurnberger, John I.; Liu, Yunlong; Edenberg, Howard J.; Porjesz, Bernice; Agrawal, Arpana; Foroud, Tatiana; Schuckit, Marc; Plawecki, Martin H.; Bucholz, Kathleen K.; McCutcheon, Vivia V.; Medical and Molecular Genetics, School of Medicine
    Background: In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGSAUD ) was positively associated with AUD severity as measured by DSM-5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGSAUD would be negatively associated with remission. Methods: Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12-month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non-abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non-abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. Results: In COGA EA, PGSAUD was negatively associated with 12-month and non-abstinent remission (p ≤ 0.013, βs between -0.15 and -0.10) after adjusting for all covariates. In contrast to the COGA findings, PGSAUD was positively associated with remission (p = 0.004, β = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, β = 0.15). Conclusions: PGSAUD was negatively associated with 12-month and non-abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol-related health conditions that manifested in later life.
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    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 Medicine
    Background: 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.
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    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 Health
    Background: 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.
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    Binge and High-Intensity Drinking – Associations with Intravenous Alcohol Self-Administration and Underlying Risk Factors
    (Wiley, 2022) Plawecki, Martin H.; Boes, Julian; Wetherill, Leah; Kosobud, Ann E.K.; Stangl, Bethany L.; Ramchandani, Vijay A.; Zimmermann, Ulrich S.; Nurnberger, John I., Jr.; Schuckit, Marc; Edenberg, Howard J.; Pandey, Gayathri; Kamarajan, Chella; Porjesz, Bernice; Foroud, Tatiana; O’Connor, Sean; Psychiatry, School of Medicine
    Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders.
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    Common biological networks underlie genetic risk for alcoholism in African- and European-American populations
    (Wiley, 2013) Kos, Mark Z.; Yan, Jia; Dick, Danielle M.; Agrawal, Arpana; Bucholz, Kathleen K.; Rice, John P.; Johnson, Eric O.; Schuckit, Marc; Kuperman, Sam; Kramer, John; Goate, Alison M.; Tischfield, Jay A.; Foroud, Tatiana; Nurnberger, John, Jr.; Hesselbrock, Victor; Porjesz, Bernice; Bierut, Laura J.; Edenberg, Howard J.; Almasy, Laura; Medical and Molecular Genetics, School of Medicine
    Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome-wide association studies (GWAS) account for only a small fraction of its overall risk, with effects varying across ethnic groups. Here we investigate the genetic architecture of alcoholism and report on the extent to which common, genome-wide SNPs collectively account for risk of AD in two US populations, African-Americans (AAs) and European-Americans (EAs). Analyzing GWAS data for two independent case-control sample sets, we compute polymarker scores that are significantly associated with alcoholism (P = 1.64 × 10(-3) and 2.08 × 10(-4) for EAs and AAs, respectively), reflecting the small individual effects of thousands of variants derived from patterns of allelic architecture that are population specific. Simulations show that disease models based on rare and uncommon causal variants (MAF < 0.05) best fit the observed distribution of polymarker signals. When scoring bins were annotated for gene location and examined for constituent biological networks, gene enrichment is observed for several cellular processes and functions in both EA and AA populations, transcending their underlying allelic differences. Our results reveal key insights into the complex etiology of AD, raising the possibility of an important role for rare and uncommon variants, and identify polygenic mechanisms that encompass a spectrum of disease liability, with some, such as chloride transporters and glycine metabolism genes, displaying subtle, modifying effects that are likely to escape detection in most GWAS designs.
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    Density and Dichotomous Family History Measures of Alcohol Use Disorder as Predictors of Behavioral and Neural Phenotypes: A Comparative Study Across Gender and Race/Ethnicity
    (Wiley, 2020-03) Pandey, Gayathri; Seay, Michael J.; Meyers, Jacquelyn L.; Chorlian, David B.; Pandey, Ashwini K.; Kamarajan, Chella; Ehrenberg, Morton; Pitti, Daniel; Kinreich, Sivan; de Viteri, Stacey Subbie-Saenz; Acion, Laura; Anokhin, Andrey; Bauer, Lance; Chan, Grace; Edenberg, Howard; Hesselbrock, Victor; Kuperman, Samuel; McCutcheon, Vivia V.; Bucholz, Kathleen K.; Schuckit, Marc; Porjesz, Bernice; Biochemistry and Molecular Biology, School of Medicine
    Background: Family history (FH) is an important risk factor for the development of alcohol use disorder (AUD). A variety of dichotomous and density measures of FH have been used to predict alcohol outcomes; yet, a systematic comparison of these FH measures is lacking. We compared 4 density and 4 commonly used dichotomous FH measures and examined variations by gender and race/ethnicity in their associations with age of onset of regular drinking, parietal P3 amplitude to visual target, and likelihood of developing AUD. Methods: Data from the Collaborative Study on the Genetics of Alcoholism (COGA) were utilized to compute the density and dichotomous measures. Only subjects and their family members with DSM-5 AUD diagnostic information obtained through direct interviews using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) were included in the study. Area under receiver operating characteristic curves were used to compare the diagnostic accuracy of FH measures at classifying DSM-5 AUD diagnosis. Logistic and linear regression models were used to examine associations of FH measures with alcohol outcomes. Results: Density measures had greater diagnostic accuracy at classifying AUD diagnosis, whereas dichotomous measures presented diagnostic accuracy closer to random chance. Both dichotomous and density measures were significantly associated with likelihood of AUD, early onset of regular drinking, and low parietal P3 amplitude, but density measures presented consistently more robust associations. Further, variations in these associations were observed such that among males (vs. females) and Whites (vs. Blacks), associations of alcohol outcomes with density (vs. dichotomous) measures were greater in magnitude. Conclusions: Density (vs. dichotomous) measures seem to present more robust associations with alcohol outcomes. However, associations of dichotomous and density FH measures with different alcohol outcomes (behavioral vs. neural) varied across gender and race/ethnicity. These findings have great applicability for alcohol research examining FH of AUD.
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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.