Browsing by Author "Barr, Peter B."
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Item Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts(Springer, 2022-10-04) Barr, Peter B.; Driver, Morgan N.; Kuo, Sally I-Chun; Stephenson, Mallory; Aliev, Fazil; Linnér, Richard Karlsson; Marks, Jesse; Anokhin, Andrey P.; Bucholz, Kathleen; Chan, Grace; Edenberg, Howard J.; Edwards, Alexis C.; Francis, Meredith W.; Hancock, Dana B.; Harden, K. Paige; Kamarajan, Chella; Kaprio, Jaakko; Kinreich, Sivan; Kramer, John R.; Kuperman, Samuel; Latvala, Antti; Meyers, Jacquelyn L.; Palmer, Abraham A.; Plawecki, Martin H.; Porjesz, Bernice; Rose, Richard J.; Schuckit, Marc A.; Salvatore, Jessica E.; Dick , Danielle M.; Medical and Molecular Genetics, School of MedicineSubstance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.Item Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence(medRxiv, 2023-04-29) Barr, Peter B.; Neale, Zoe; Schulman, Jessica; Mullins, Niamh; Zhang, Jian; Chorlian, David B.; Kamarajan, Chella; Kinreich, Sivan; Pandey, Ashwini K.; Pandey, Gayathri; Saenz de Viteri, Stacey; Acion, Laura; Bauer, Lance; Bucholz, Kathleen K.; Chan, Grace; Chao, Michael; Dick, Danielle M.; Edenberg, Howard J.; Foroud, Tatiana; Goate, Alison; Hesselbrock, Victor; Johnson, Emma C.; Kramer, John; Lai, Dongbing; Plawecki, Martin H.; Salvatore, Jessica E.; Wetherill, Leah; Agrawal, Arpana; Porjesz, Bernice; Meyers, Jacquelyn L.; Medical and Molecular Genetics, School of MedicineResearch has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder, despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) explored clinical risk factors associated with SA, 2) conducted a genome-wide association study of SA, 3) examined whether individuals with a SA had elevated polygenic scores for comorbid psychiatric conditions (e.g., alcohol use disorders, lifetime suicide attempt, and depression), and 4) explored differences in electroencephalogram neural functional connectivity between those with and without a SA. One gene-based finding emerged, RFX3 (Regulatory Factor X, located on 9p24.2) which had supporting evidence in prior research of SA among individuals with major depression. Only the polygenic score for suicide attempts was associated with reporting a suicide attempt (OR = 1.20, 95% CI = 1.06, 1.37). Lastly, we observed decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences among those participants who reported a SA relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.Item Defining Suicidal Thought and Behavior Phenotypes for Genetic Studies(medRxiv, 2024-07-29) Monson, Eric T.; Colbert, Sarah M. C.; Andreassen, Ole A.; Ayinde, Olatunde O.; Bejan, Cosmin A.; Ceja, Zuriel; Coon, Hilary; DiBlasi, Emily; Izotova, Anastasia; Kaufman, Erin A.; Koromina, Maria; Myung, Woojae; Nurnberger, John I., Jr.; Serretti, Alessandro; Smoller, Jordan W.; Stein, Murray B.; Zai, Clement C.; Suicide Working Group of the Psychiatric Genomics Consortium; Aslan, Mihaela; Barr, Peter B.; Bigdeli, Tim B.; Harvey, Philip D.; Kimbrel, Nathan A.; Patel, Pujan R.; Cooperative Studies Program (CSP) #572; Ruderfer, Douglas; Docherty, Anna R.; Mullins, Niamh; Mann, J. John; Psychiatry, School of MedicineBackground: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.Item Integration of evidence across human and model organism studies: A meeting report(Wiley, 2021-04-23) Palmer, Rohan H.C.; Johnson, Emma C.; Won, Hyejung; Polimanti, Renato; Kapoor, Manav; Chitre, Apurva; Bogue, Molly A.; Benca-Bachman, Chelsie E.; Parker, Clarissa C.; Verm, Anurag; Reynolds, Timothy; Ernst, Jason; Bray, Michael; Kwon, Soo Bin; Lai, Dongbing; Quach, Bryan C.; Gaddis, Nathan C.; Saba, Laura; Chen, Hao; Hawrylycz, Michael; Zhang, Shan; Zhou, Yuan; Mahaffey, Spencer; Fischer, Christian; Sanchez-Roige, Sandra; Bandrowski, Anita; Lu, Qing; Shen, Li; Philip, Vivek; Gelernter, Joel; Bierut, Laura J.; Hancock, Dana B.; Edenberg, Howard J.; Johnson, Eric O.; Nestler, Eric J.; Barr, Peter B.; Prins, Pjotr; Smith, Desmond J.; Akbarian, Schahram; Thorgeirsson, Thorgeir; Walton, Dave; Baker, Erich; Jacobson, Daniel; Palmer, Abraham A.; Miles, Michael; Chesler, Elissa J.; Emerson, Jake; Agrawal, Arpana; Martone, Maryann; Williams, Robert W.; Medical and Molecular Genetics, School of MedicineThe National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.Item Mapping Pathways by which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use(Springer, 2021) Kuo, Sally I-Chun; Salvatore, Jessica E.; Barr, Peter B.; Aliev, Fazil; Anokhin, Andrey; Bucholz, Kathleen K.; Chan, Grace; Edenberg, Howard J.; Hesselbrock, Victor; Kamarajan, Chella; Kramer, John R.; Lai, Dongbing; Mallard, Travis T.; Nurnberger, John I., Jr.; Pandey, Gayathri; Plawecki, Martin H.; Sanchez-Roige, Sandra; Waldman, Irwin; Palmer, Abraham A.; Externalizing Consortium; Dick, Danielle M.; Biochemistry and Molecular Biology, School of MedicineGenetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene-environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent externalizing behavior across two time-points in a high-risk longitudinal sample of 1,200 adolescents (764 European and 436 African ancestry; Mage = 12.99) from the Collaborative Study on the Genetics of Alcoholism. Results from multivariate path analysis indicated that externalizing polygenic scores were directly associated with adolescent externalizing behavior but also indirectly via peer substance use, in the European ancestry sample. No significant polygenic association nor indirect effects of genetic risk were observed in the African ancestry group, likely due to more limited power. Our findings underscore the importance of gene-environment interplay and suggest peer substance use may be a mechanism through which genetic risk influences adolescent externalizing behavior.Item Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System(American Medical Association, 2022-09-14) Bigdeli, Tim B.; Voloudakis, Georgios; Barr, Peter B.; Gorman, Bryan R.; Genovese, Giulio; Peterson, Roseann E.; Burstein, David E.; Velicu, Vlad I.; Li, Yuli; Gupta, Rishab; Mattheisen, Manuel; Tomasi, Simone; Rajeevan, Nallakkandi; Sayward, Frederick; Radhakrishnan, Krishnan; Natarajan, Sundar; Malhotra, Anil K.; Shi, Yunling; Zhao, Hongyu; Kosten, Thomas R.; Concato, John; O'Leary, Timothy J.; Przygodzki, Ronald; Gleason, Theresa; Pyarajan, Saiju; Brophy, Mary; Huang, Grant D.; Muralidhar, Sumitra; Gaziano, J. Michael; Aslan, Mihaela; Fanous, Ayman H.; Harvey, Philip D.; Roussos, Panos; Cooperative Studies Program (CSP); Million Veteran Program (MVP); Psychiatry, School of MedicineImportance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies. Design, setting, and participants: Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. Main outcomes and measures: Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Results: Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P < 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. Conclusions and relevance: Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.Item Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features(MDPI, 2023-05-18) Kamarajan, Chella; Pandey, Ashwini K.; Chorlian, David B.; Meyers, Jacquelyn L.; Kinreich, Sivan; Pandey, Gayathri; Subbie-Saenz de Viteri, Stacey; Zhang, Jian; Kuang, Weipeng; Barr, Peter B.; Aliev, Fazil; Anokhin, Andrey P.; Plawecki, Martin H.; Kuperman, Samuel; Almasy, Laura; Merikangas, Alison; Brislin, Sarah J.; Bauer, Lance; Hesselbrock, Victor; Chan, Grace; Kramer, John; Lai, Dongbing; Hartz, Sarah; Bierut, Laura J.; McCutcheon, Vivia V.; Bucholz, Kathleen K.; Dick, Danielle M.; Schuckit, Marc A.; Edenberg, Howard J.; Porjesz, Bernice; Psychiatry, School of MedicineMemory problems are common among older adults with a history of alcohol use disorder (AUD). Employing a machine learning framework, the current study investigates the use of multi-domain features to classify individuals with and without alcohol-induced memory problems. A group of 94 individuals (ages 50–81 years) with alcohol-induced memory problems (the memory group) were compared with a matched control group who did not have memory problems. The random forests model identified specific features from each domain that contributed to the classification of the memory group vs. the control group (AUC = 88.29%). Specifically, individuals from the memory group manifested a predominant pattern of hyperconnectivity across the default mode network regions except for some connections involving the anterior cingulate cortex, which were predominantly hypoconnected. Other significant contributing features were: (i) polygenic risk scores for AUD, (ii) alcohol consumption and related health consequences during the past five years, such as health problems, past negative experiences, withdrawal symptoms, and the largest number of drinks in a day during the past twelve months, and (iii) elevated neuroticism and increased harm avoidance, and fewer positive “uplift” life events. At the neural systems level, hyperconnectivity across the default mode network regions, including the connections across the hippocampal hub regions, in individuals with memory problems may indicate dysregulation in neural information processing. Overall, the study outlines the importance of utilizing multidomain features, consisting of resting-state brain connectivity data collected ~18 years ago, together with personality, life experiences, polygenic risk, and alcohol consumption and related consequences, to predict the alcohol-related memory problems that arise in later life.Item Sibling Comparisons Elucidate the Associations between Educational Attainment Polygenic Scores and Alcohol, Nicotine, and Cannabis(Wiley, 2020-02) Salvatore, Jessica E.; Barr, Peter B.; Stephenson, Mallory; Aliev, Fazil; I-Chun Kuo, Sally; Su, Jinni; Agrawal, Arpana; Almasy, Laura; Bierut, Laura; Bucholz, Kathleen; Chan, Grace; Edenberg, Howard J.; Johnson, Emma C.; McCutcheon, Vivia V.; Meyers, Jacquelyn L.; Schuckit, Marc; Tischfield, Jay; Wetherill, Leah; Dick, Danielle M.; Biochemistry and Molecular Biology, School of MedicineBackground and aims: The associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis). Design: Polygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families. Setting: Six sites in the United States. Participants: European ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample. Measurements: Outcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment. Findings: In polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R2 ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R2 0.13-0.20%). Conclusions: Individuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education).Item The role of parental genotype in the intergenerational transmission of externalizing behavior: Evidence for genetic nurturance(Cambridge University Press, 2022-10-06) Kuo, Sally I-Chun; Poore, Holly E.; Barr, Peter B.; Chirico, Isabella S.; Aliev, Fazil; Bucholz, Kathleen K.; Chan, Grace; Kamarajan, Chella; Kramer, John R.; McCutcheon, Vivia V.; Plawecki, Martin H.; Dick, Danielle M.; Psychiatry, School of MedicineThe purpose of this study was to examine possible pathways by which genetic risk associated with externalizing is transmitted in families. We used molecular data to disentangle the genetic and environmental pathways contributing to adolescent externalizing behavior in a sample of 1,111 adolescents (50% female; 719 European and 392 African ancestry) and their parents from the Collaborative Study on the Genetics of Alcoholism. We found evidence for genetic nurture such that parental externalizing polygenic scores were associated with adolescent externalizing behavior, over and above the effect of adolescents’ own externalizing polygenic scores. Mediation analysis indicated that parental externalizing psychopathology partly explained the effect of parental genotype on children’s externalizing behavior. We also found evidence for evocative gene-environment correlation, whereby adolescent externalizing polygenic scores were associated with lower parent–child communication, less parent–child closeness, and lower parental knowledge, controlling for parental genotype. These effects were observed among participants of European ancestry but not African ancestry, likely due to the limited predictive power of polygenic scores across ancestral background. These results demonstrate that in addition to genetic transmission, genes influence offspring behavior through the influence of parental genotypes on their children’s environmental experiences, and the role of children’s genotypes in shaping parent–child relationships.