Browsing by Author "Plawecki, Martin H."
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Item Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking(Wiley Blackwell (Blackwell Publishing), 2015-07) Kosobud, Ann E. K.; Wetherill, Leah; Plawecki, Martin H.; Kareken, David A.; Liang, Tiebing; Nurnberger, John L.; Windisch, Kyle; Xuei, Xiaoling; Edenberg, Howard J.; Foroud, Tatiana M.; O’Connor, Sean J.; Department of Psychiatry, IU School of MedicineBACKGROUND: Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. METHODS: One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. RESULTS: Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. CONCLUSIONS: Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.Item Adolescent women induce lower blood alcohol levels than men in a laboratory alcohol self-administration experiment(Wiley, 2016-08) Jünger, Elisabeth; Gan, Gabriela; Mick, Inge; Seipt, Christian; Markovic, Alexandra; Sommer, Christian; Plawecki, Martin H.; O'Connor, Sean; Smolka, Michael N.; Zimmermann, Ulrich S.; Psychiatry, School of MedicineBackground Adolescence is a critical period for the development of alcohol use disorders; drinking habits are rather unstable and genetic influences, such as male sex and a positive Family History of alcoholism (FH), are often masked by environmental factors such as peer pressure. Methods We investigated how sex and FH modulate alcohol use in a sample of 18-19-year-olds from the Dresden Longitudinal Study on Alcohol use in Young Adults (D-LAYA). Adolescents reported their real-life drinking in a TimeLine Follow-Back (TLFB) interview. They subsequently completed a training and an experimental session of free-access intravenous Alcohol Self-Administration (i.v. ASA) using the computer-assisted alcohol infusion system in order to control for environmental cues as well as for biological differences in alcohol pharmacokinetics. During i.v. ASA, we assessed subjective alcohol effects at eight time points. Results Women reported significantly less real-life drinking than men and achieved significantly lower mean arterial Blood Alcohol Concentrations (aBACs) in the laboratory. At the same time, women reported greater sedation relative to men and rated negative effects as high as did men. A positive FH was associated with lower real-life drinking in men but not in women. In the laboratory, FH was not linked to i.v. ASA. Greater real-life drinking was significantly positively associated with higher mean aBACs in the laboratory, and all i.v. ASA indices were highly correlated across the two sessions. Conclusions We conclude that adolescent women chose lower aBACs because they experienced adverse alcohol effects, namely sedation and negative effects, at lower aBACs than men. A positive FH was not apparent as risk factor for drinking in our young sample. The i.v. ASA method demonstrated good external validity as well as test-retest reliability, the latter indicating that a separate training session is not required when employing the i.v. ASA paradigm.Item Alcohol Affects the P3 Component of an Adaptive Stop Signal Task ERP(Elsevier, 2017) Plawecki, Martin H.; Windisch, Kyle A.; Wetherill, Leah; Kosubud, Ann E. K.; Dzemidzic, Mario; Kareken, David A.; O'Connor, Sean J.; Department of Psychiatry, School of MedicineBACKGROUND The P3 component of the event-related potential (ERP) has been particularly useful in alcohol research for identifying endophenotypes of alcohol use disorder (AUD) risk in sober subjects. However, practice and/or fatigue reduces P3 amplitude, limiting the ability to ascertain acute and adaptive effects of alcohol exposure. Here, we report acute alcohol effects on P3 amplitude and latency using an adaptive stop signal task (aSST). METHODS One hundred and forty eight nondependent moderate to heavy social drinkers, age 21 to 27, participated in 2 single-blind, alcohol or placebo, counterbalanced sessions approximately one week apart. During each session, subjects performed an adaptive stop signal task (aSST) at (1) baseline, (2) upon reaching the target 60 mg/dL breath alcohol concentration or at the equivalent time during the placebo session, and (3) approximately 135 minutes later while the breath alcohol concentration was clamped. Here, we report on differences between baseline and first subsequent measurements across the experimental sessions. During each aSST run, the stop signal delay (SSD, the time between stop and go signals) adjusted trial-by-trial based on the subject’s performance. RESULTS The aSST reliably generated a STOP P3 component that did not change significantly with repeated task performance. The pre-infusion SSD distribution was bimodal, with mean values several hundred msec apart (FAST: 153 msec and SLOW: 390 msec). This suggested different response strategies: FAST SSD favoring “going” over “stopping,” and SLOW SSD favoring “stopping” over “going”. Exposure to alcohol at 60 mg/dL differentially affected the amplitude and latency of the STOP P3 according to SSD group. Alcohol significantly reduced P3 amplitude in the SLOW SSD compared to FAST SSD group, but significantly increased P3 latency in the FAST SSD compared to SLOW SSD group. CONCLUSIONS The aSST is a robust and sensitive task for detecting alcohol induced changes in inhibition behavior as measured by the P3 component in a within subject design. Alcohol was associated with P3 component changes which varied by SSD group, suggesting a differential effect as a function of task strategy. Overall, the data support the potential utility of the aSST in the detection of alcohol response related AUD risk.Item 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 MedicineImportance: 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.Item Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users(Oxford University Press, 2023) Johnson, Emma C.; Colbert, Sarah M. C.; Jeffries, Paul W.; Tillman, Rebecca; Bigdeli, Tim B.; Karcher, Nicole R.; Chan, Grace; Kuperman, Samuel; Meyers, Jacquelyn L.; Nurnberger, John I.; Plawecki, Martin H.; Degenhardt, Louisa; Martin, Nicholas G.; Kamarajan, Chella; Schuckit, Marc A.; Murray, Robin M.; Dick, Danielle M.; Edenberg, Howard J.; D'Souza, Deepak Cyril; Di Forti, Marta; Porjesz, Bernice; Nelson, Elliot C.; Agrawal, Arpana; Medical and Molecular Genetics, School of MedicineBackground and hypothesis: Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. Study design: We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). Study results: Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. Conclusions: Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use.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 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 MedicineSome 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.Item Brain response in heavy drinkers during cross-commodity alcohol and money discounting with potentially real rewards: A preliminary study(Elsevier, 2023-07-06) Lungwitz, Elizabeth A.; Dzemidzic, Mario; Shen, Yitong I.; Plawecki, Martin H.; Oberlin, Brandon G.; Psychiatry, School of MedicineBackground: Alcohol use disorder (AUD) is associated with exaggerated preference for immediate rewards, a candidate endophenotype for use disorders. Addiction symptomology is often well-described by the preference for immediate intoxication over other delayed prosocial rewards. We measured brain activation in AUD-implicated regions during a cross-commodity delay discounting (CCD) task with choices for immediate alcohol and delayed money. Methods: Heavy drinkers (n=24) experienced a brief intravenous alcohol infusion prime, regained sobriety, then chose between 'One Shot' and delayed money in an adjusting delay CCD task (sober and intoxicated); also during fMRI (sober). Participants also performed a behavioral sensation seeking task and completed self-report inventories of other risk factors. We assessed brain activation to choices representing immediate intoxication versus delayed money rewards in a priori regions of interest defined within the framework of Addictions NeuroImaging Assessment. Results: Activation to CCD choice versus control trials activated paralimbic and ventral frontal cortical regions, including orbital and medial prefrontal cortex, posterior cingulate/retrosplenial cortex, angular and superior frontal gyri. We detected no differences between immediate or delayed choices. Left medial orbitofrontal cortex activation correlated with alcohol-induced wanting for alcohol; females showed greater activation than males. Behavioral sensation seeking correlated with right nucleus accumbens task engagement. Conclusions: Alcohol decision-making elicited activation in regions governing reward, introspection, and executive decision-making in heavy drinkers, demonstrating the utility of laboratory tasks designed to better model real-world choice. Our findings suggest that the brain processes subserving immediate and delayed choices are mostly overlapping, even with varied commodities.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.