Browsing by Author "Kamarajan, Chella"
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Item 5. Collaborative Study on the Genetics of Alcoholism: Functional genomics(Wiley, 2023) Gameiro-Ros, Isabel; Popova, Dina; Prytkova, Iya; Pang, Zhiping P.; Liu, Yunlong; Dick, Danielle; Bucholz, Kathleen K.; Agrawal, Arpana; Porjesz, Bernice; Goate, Alison M.; Xuei, Xiaoling; Kamarajan, Chella; COGA Collaborators; Tischfield, Jay A.; Edenberg, Howard J.; Slesinger, Paul A.; Hart, Ronald P.; Medical and Molecular Genetics, School of MedicineAlcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.Item A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency(Springer, 2024) Thomas, Nathaniel S.; Gillespie, Nathan A.; Chan, Grace; Edenberg, Howard J.; Kamarajan, Chella; I-Chun Kuo, Sally; Miller, Alex P.; Nurnberger, John I., Jr.; Tischfield, Jay; Dick, Danielle M.; Salvatore, Jessica E.; Medical and Molecular Genetics, School of MedicineContemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.Item Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons(Springer Nature, 2023) Popova, Dina; Gameiro-Ros, Isabel; Youssef, Mark M.; Zalamea, Petronio; Morris, Ayeshia D.; Prytkova, Iya; Jadali, Azadeh; Kwan, Kelvin Y.; Kamarajan, Chella; Salvatore, Jessica E.; Xuei, Xiaoling; Chorlian, David B.; Porjesz, Bernice; Kuperman, Samuel; Dick, Danielle M.; Goate, Alison; Edenberg, Howard J.; Tischfield, Jay A.; Pang, Zhiping P.; Slesinger, Paul A.; Hart, Ronald P.; Medical and Molecular Genetics, School of MedicineSynonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium channel subunit 2 (GIRK2), have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcohol use disorder (AUD). To identify molecular and cellular mechanisms while retaining the appropriate genetic background, we generated induced excitatory glutamatergic neurons (iN) from iPSCs derived from four AUD-diagnosed subjects with KCNJ6 variants ("Affected: AF") and four control subjects without variants ("Unaffected: UN"). Neurons were analyzed for changes in gene expression, morphology, excitability and physiological properties. Single-cell RNA sequencing suggests that KCNJ6 AF variant neurons have altered patterns of synaptic transmission and cell projection morphogenesis. Results confirm that AF neurons express lower levels of GIRK2, have greater neurite area, and elevated excitability. Interestingly, exposure to intoxicating concentrations of ethanol induces GIRK2 expression and reverses functional effects in AF neurons. Ectopic overexpression of GIRK2 alone mimics the effect of ethanol to normalize induced excitability. We conclude that KCNJ6 variants decrease GIRK2 expression and increase excitability and that this effect can be minimized or reduced with ethanol.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 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 Alcohol-Related, Drug-Related, and Non-Substance-Related Aggression: Three Facets of a Single Construct or Three Distinct Constructs?(Wiley, 2020-09) Chester, David S.; Bucholz, Kathleen K.; Chan, Grace; Kamarajan, Chella; Pandey, Ashwini K.; Wetherill, Leah; Kramer, John R.; Nurnberger, John I., Jr.; Salvatore, Jessica E.; Dick, Danielle M.; Medical and Molecular Genetics, School of MedicineBackground: Aggression often occurs alongside alcohol and drug misuse. However, it is not clear whether the latent and manifest relations among alcohol-related, drug-related, and non-substance-related aggression are separate manifestations of a single construct or instead are 3 distinct constructs. Methods: To examine these associations, we conducted a preregistered analysis of 13,490 participants in the Collaborative Study on the Genetics of Alcoholism. In a structured interview, participants reported their lifetime perpetration of these 3 aggression phenotypes. Results: The data were better fit by a model that treated these aggression phenotypes as 3 distinct latent factors, as compared to models in which the items all loaded onto 1 ("general") or 2 ("substance-related" and "non-substance-related") aggression factors. This 3-factor model fit better for men than women. Subsequent exploratory analyses then showed that among these 3 factors, alcohol-related aggression explained the variance of overall aggression better than the other 2 factors. Conclusions: Our findings suggest that these 3 forms of aggression are distinct phenotypes (especially among men). Yet, people's alcohol-related aggression can accurately characterize their overall aggressive tendencies across these domains. Future research will benefit from articulating the unique and shared pathways and risk factors underlying each of these facets of aggression.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 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 MedicineBackground: 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.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.