546 results on '"Lai, Dongbing"'
Search Results
2. Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease
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Hop, Paul J., Lai, Dongbing, Keagle, Pamela J., Baron, Desiree M., Kenna, Brendan J., Kooyman, Maarten, Shankaracharya, Halter, Cheryl, Straniero, Letizia, Asselta, Rosanna, Bonvegna, Salvatore, Soto-Beasley, Alexandra I., Wszolek, Zbigniew K., Uitti, Ryan J., Isaias, Ioannis Ugo, Pezzoli, Gianni, Ticozzi, Nicola, Ross, Owen A., Veldink, Jan H., Foroud, Tatiana M., Kenna, Kevin P., and Landers, John E.
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- 2024
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3. Diagnostic Criteria for Identifying Individuals at High Risk of Progression From Mild or Moderate to Severe Alcohol Use Disorder
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Miller, Alex P, Kuo, Sally I-Chun, Johnson, Emma C, Tillman, Rebecca, Brislin, Sarah J, Dick, Danielle M, Kamarajan, Chella, Kinreich, Sivan, Kramer, John, McCutcheon, Vivia V, Plawecki, Martin H, Porjesz, Bernice, Schuckit, Marc A, Salvatore, Jessica E, Edenberg, Howard J, Bucholz, Kathleen K, Meyers, Jaquelyn L, Agrawal, Arpana, Hesselbrock, Victor, Foroud, Tatiana, Liu, Yunlong, Kuperman, Samuel, Pandey, Ashwini K, Bierut, Laura J, Rice, John, Tischfield, Jay A, Hart, Ronald P, Almasy, Laura, Goate, Alison, Slesinger, Paul, Scott, Denise M, Bauer, Lance O, Nurnberger, John I, Wetherill, Leah, Xuei, Xiaoling, Lai, Dongbing, O'Connor, Sean J, Chan, Grace, Chorlian, David B, Zhang, Jian, Barr, Peter B, Pandey, Gayathri, Mullins, Niamh, Anokhin, Andrey P, Hartz, Sarah, Saccone, Scott, Moore, Jennifer C, Aliev, Fazil, Pang, Zhiping, Merikangas, Alison, Chin, Hemin, and Parsian, Abbas
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Biomedical and Clinical Sciences ,Clinical Research ,Alcoholism ,Alcohol Use and Health ,Substance Misuse ,Brain Disorders ,Mental Health ,Prevention ,Aetiology ,2.1 Biological and endogenous factors ,Mental health ,Good Health and Well Being ,Collaborative Study on the Genetics of Alcoholism ,Biomedical and clinical sciences ,Health sciences - Abstract
ImportanceCurrent Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) diagnoses of substance use disorders rely on criterion count-based approaches, disregarding severity grading indexed by individual criteria.ObjectiveTo examine correlates of alcohol use disorder (AUD) across count-based severity groups (ie, mild, moderate, mild-to-moderate, severe), identify specific diagnostic criteria indicative of greater severity, and evaluate whether specific criteria within mild-to-moderate AUD differentiate across relevant correlates and manifest in greater hazards of severe AUD development.Design, setting, and participantsThis cohort study involved 2 cohorts from the family-based Collaborative Study on the Genetics of Alcoholism (COGA) with 7 sites across the United States: cross-sectional (assessed 1991-2005) and longitudinal (assessed 2004-2019). Statistical analyses were conducted from December 2022 to June 2023.Main outcomes and measuresSociodemographic, alcohol-related, psychiatric comorbidity, brain electroencephalography (EEG), and AUD polygenic score measures as correlates of DSM-5 AUD levels (ie, mild, moderate, severe) and criterion severity-defined mild-to-moderate AUD diagnostic groups (ie, low-risk vs high-risk mild-to-moderate).ResultsA total of 13 110 individuals from the cross-sectional COGA cohort (mean [SD] age, 37.8 [14.2] years) and 2818 individuals from the longitudinal COGA cohort (mean baseline [SD] age, 16.1 [3.2] years) were included. Associations with alcohol-related, psychiatric, EEG, and AUD polygenic score measures reinforced the role of increasing criterion counts as indexing severity. Yet within mild-to-moderate AUD (2-5 criteria), the presence of specific high-risk criteria (eg, withdrawal) identified a group reporting heavier drinking and greater psychiatric comorbidity even after accounting for criterion count differences. In longitudinal analyses, prior mild-to-moderate AUD characterized by endorsement of at least 1 high-risk criterion was associated with more accelerated progression to severe AUD (adjusted hazard ratio [aHR], 11.62; 95% CI, 7.54-17.92) compared with prior mild-to-moderate AUD without endorsement of high-risk criteria (aHR, 5.64; 95% CI, 3.28-9.70), independent of criterion count.Conclusions and relevanceIn this cohort study of a combined 15 928 individuals, findings suggested that simple count-based AUD diagnostic approaches to estimating severe AUD vulnerability, which ignore heterogeneity among criteria, may be improved by emphasizing specific high-risk criteria. Such emphasis may allow better focus on individuals at the greatest risk and improve understanding of the development of AUD.
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- 2023
4. Do personality characteristics predict future alcohol problems after considering current demography, substance use, and alcohol response?
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Schuckit, Marc A, Smith, Tom L, Danko, George, Bucholz, Kathleen K, Hesselbrock, Victor, Hesselbrock, Michie, Kuperman, Samuel, Kramer, John, Nurnberger, John I, Lai, Dongbing, Chan, Grace, Kamarajan, Chella, Kuo, Sally, Dick, Danielle M, Tear, Jake, Mendoza, Lee Anne, Edenberg, Howard J, and Porjesz, Bernice
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Biological Psychology ,Social and Personality Psychology ,Psychology ,Substance Misuse ,Behavioral and Social Science ,Alcoholism ,Alcohol Use and Health ,Clinical Research ,Mental Health ,Prevention ,Brain Disorders ,2.3 Psychological ,social and economic factors ,Aetiology ,Mental health ,Good Health and Well Being ,alcohol ,alcohol response ,AUD problems ,personality ,Clinical Sciences ,Neurosciences ,Substance Abuse ,Clinical sciences ,Biological psychology ,Clinical and health psychology - Abstract
BackgroundSeveral personality traits predict future alcohol problems but also relate to demographic and substance-related variables that themselves correlate with later adverse alcohol outcomes. Few prospective studies have evaluated whether personality measures predict alcohol problems after considering current demographic and substance-related variables.MethodsData from 414 drinkers without alcohol use disorder (AUD) from the Collaborative Study on the Genetics of Alcoholism (average age 20, 44% male) were followed over an average of 9 years. Time 1 (baseline) demography, AUD family history (FH), substance use and problems, and psychiatric histories were gathered using a standardized interview; the Level of Response (LR) to alcohol was measured by the Self-Report of the Effects of alcohol (SRE) questionnaire; and seven personality dimensions were extracted from the NEO Five-Factor Personality, Barratt, and Zuckerman scales. Analyses involved product-moment correlations of each baseline measure with the highest number of DSM-IV AUD criteria endorsed in any follow-up period, and hierarchical regression analyses evaluated whether the personality domains added significantly to the prediction of the outcome after adjusting for other baseline variables.ResultsSignificant correlations with the outcome were observed for baseline age, sex, length of follow-up, AUD family history, past cannabis use, and all alcohol-related baseline variables, including SRE-based LR, but not prior mood or anxiety disorders. All personality characteristics except extraversion also correlated with outcomes. A hierarchical regression analysis that included all relevant personality scores together demonstrated significant contributions to the prediction of future alcohol problems for demographics in Step 1; demographics and most baseline alcohol items, including response level, in Step 2; and cannabis use in Step 3; after which demographics, LR, baseline alcohol problems, cannabis use, and higher sensation seeking added significantly in Step 4. Regression for each personality domain separately revealed significant contributions to Step 4 for all personality domains except openness. Lower levels of response to alcohol added significantly to all regression analyses.ConclusionsMost tested personality scores and lower levels of response to alcohol contributed to predictions of later alcohol problems even after considering baseline demographic and substance use measures.
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- 2023
5. Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features
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Kamarajan, Chella, Pandey, Ashwini K, Chorlian, David B, Meyers, Jacquelyn L, Kinreich, Sivan, Pandey, Gayathri, de Viteri, Stacey Subbie-Saenz, 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, and Porjesz, Bernice
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Basic Behavioral and Social Science ,Brain Disorders ,Behavioral and Social Science ,Substance Misuse ,Neurosciences ,Prevention ,Mental Health ,Alcoholism ,Alcohol Use and Health ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Mental health ,Good Health and Well Being ,alcohol use disorder ,EEG source functional connectivity ,default mode network ,alcohol-related memory problems ,random forests ,Psychology ,Cognitive Sciences - Abstract
Memory 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.
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- 2023
6. High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk
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Nurnberger, John I, Wang, Yumin, Zang, Yong, Lai, Dongbing, Wetherill, Leah, Edenberg, Howard J, Aliev, Fazil, Plawecki, Martin H, Chorlian, David, Chan, Grace, Bucholz, Kathleen, Bauer, Lance, Kamarajan, Chella, Salvatore, Jessica E, Kapoor, Manav, Hesselbrock, Victor, Dick, Danielle, Bierut, Laura, McCutcheon, Vivia, Meyers, Jacquelyn L, Porjesz, Bernice, Kramer, John, Kuperman, Samuel, Kinreich, Sivan, Anokhin, Andrey P, Porjesz, B, Hesselbrock, V, Foroud, T, Agrawal, A, Dick, D, Edenberg, HJ, Nurnberger, J, Liu, Y, Kuperman, S, Kramer, J, Meyers, J, Kamarajan, C, Pandey, A, Bierut, L, Rice, J, Bucholz, K, Schuckit, M, Tischfield, J, Brooks, A, Hart, R, Almasy, L, Salvatore, J, Goate, A, Kapoor, M, Slesinger, P, Scott, D, Bauer, L, Wetherill, L, Xuei, X, Lai, D, O’Connor, S, Plawecki, M, Zang, Y, Acion, L, Chan, G, Chorlian, DB, Zhang, J, Kinreich, S, Pandey, G, Chao, M, Anokhin, A, McCutcheon, V, Saccone, S, Aliev, F, Barr, P, Chin, H, and Parsian, A
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Epidemiology ,Health Sciences ,Prevention ,Substance Misuse ,Underage Drinking ,Alcoholism ,Alcohol Use and Health ,Pediatric ,Clinical Research ,Mental health ,Good Health and Well Being ,Collaborative Study on the Genetics of Alcoholism ,Alcohol use disorder ,Clinical variables ,Polygenic risk scores ,Prediction of illness ,Receiver operating characteristics curves ,Survival analysis - Abstract
BackgroundGenome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations.MethodsA total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS.ResultsEuropean ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs (p = 3 × 10-7). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile).ConclusionsPredictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.
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- 2022
7. Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders
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Saenz de Viteri, Stacey, Zhang, Jian, Johnson, Emma C., Barr, Peter B., Edenberg, Howard J., Hesselbrock, Victor M., Nurnberger, Jr, John I., Pandey, Ashwini K., Kamarajan, Chella, Kinreich, Sivan, Tischfield, Jay A., Plawecki, Martin H., Kramer, John R., Lai, Dongbing, Kuperman, Samuel, Chan, Grace, McCutcheon, Vivia V., Bucholz, Kathleen K., Porjesz, Bernice, and Meyers, Jacquelyn L.
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- 2023
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8. Association of Heart Failure With Cognitive Decline and Development of Mild Cognitive Impairment and Dementia
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Jung, Miyeon, Apostolova, Liana G., Gao, Sujuan, Burney, Heather N., Lai, Dongbing, Saykin, Andrew J., and Pressler, Susan J.
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- 2024
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9. Alcohol Use Disorder, Psychiatric Comorbidities, Marriage and Divorce in a High-Risk Sample
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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, and Salvatore, Jessica E
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Biological Psychology ,Psychology ,Underage Drinking ,Brain Disorders ,Pediatric ,Alcoholism ,Alcohol Use and Health ,Behavioral and Social Science ,Substance Misuse ,Genetics ,2.3 Psychological ,social and economic factors ,Aetiology ,Mental health ,Good Health and Well Being ,Adult ,Alcohol-Related Disorders ,Alcoholism ,Depressive Disorder ,Major ,Divorce ,Female ,Humans ,Male ,Marijuana Abuse ,Marriage ,alcohol use disorder ,marriage ,divorce ,psychiatric comorbidities ,Collaborative Study on the Genetics of Alcoholism ,Substance Abuse ,Biological psychology ,Clinical and health psychology - Abstract
ObjectiveTo examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample.MethodParticipants 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.ResultsAmong 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.ConclusionsIn 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. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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- 2022
10. Genome-wide case-only analysis of gene-gene interactions with known Parkinson’s disease risk variants reveals link between LRRK2 and SYT10
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Aleknonytė-Resch, Milda, Trinh, Joanne, Leonard, Hampton, Delcambre, Sylvie, Leitão, Elsa, Lai, Dongbing, Smajić, Semra, Orr-Urtreger, Avi, Thaler, Avner, Blauwendraat, Cornelis, Sharma, Arunabh, Makarious, Mary B., Kim, Jonggeol Jeff, Lake, Julie, Rahmati, Pegah, Freitag-Wolf, Sandra, Seibler, Philip, Foroud, Tatiana, Singleton, Andrew B., Grünewald, Anne, Kaiser, Frank, Klein, Christine, Krawczak, Michael, and Dempfle, Astrid
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- 2023
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11. Evaluating risk for alcohol use disorder: Polygenic risk scores and family history
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Lai, Dongbing, Johnson, Emma C, Colbert, Sarah, Pandey, Gayathri, Chan, Grace, Bauer, Lance, Francis, Meredith W, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuang, Weipeng, Kuo, Sally, Kuperman, Samuel, Liu, Yunlong, McCutcheon, Vivia, Pang, Zhiping, Plawecki, Martin H, Schuckit, Marc, Tischfield, Jay, Wetherill, Leah, Zang, Yong, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, and Foroud, Tatiana
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Brain Disorders ,Prevention ,Substance Misuse ,Clinical Research ,Alcoholism ,Alcohol Use and Health ,Mental Health ,Mental health ,Good Health and Well Being ,Alcohol Drinking ,Alcoholism ,Diagnostic and Statistical Manual of Mental Disorders ,Genome-Wide Association Study ,Humans ,Risk Factors ,alcohol use disorders ,DSM-5 alcohol use disorder diagnostic criterion count ,family history of AUD ,polygenic risk scores ,Clinical Sciences ,Neurosciences ,Psychology ,Substance Abuse - Abstract
BackgroundEarly identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD.MethodsWe studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity.ResultsAUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E-05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E-08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E-04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E-11 ). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E-10 ).ConclusionsBoth PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits.
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- 2022
12. RNA alternative splicing impacts the risk for alcohol use disorder
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Li, Rudong, Reiter, Jill L., Chen, Andy B., Chen, Steven X., Foroud, Tatiana, Edenberg, Howard J., Lai, Dongbing, and Liu, Yunlong
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- 2023
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13. Inference of chronic obstructive pulmonary disease with deep learning on raw spirograms identifies new genetic loci and improves risk models
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Cosentino, Justin, Behsaz, Babak, Alipanahi, Babak, McCaw, Zachary R., Hill, Davin, Schwantes-An, Tae-Hwi, Lai, Dongbing, Carroll, Andrew, Hobbs, Brian D., Cho, Michael H., McLean, Cory Y., and Hormozdiari, Farhad
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- 2023
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14. Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans
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Lai, Dongbing, Schwantes-An, Tae-Hwi, Abreu, Marco, Chan, Grace, Hesselbrock, Victor, Kamarajan, Chella, Liu, Yunlong, Meyers, Jacquelyn L, Nurnberger, John I, Plawecki, Martin H, Wetherill, Leah, Schuckit, Marc, Zhang, Pengyue, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, and Foroud, Tatiana
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Biomedical and Clinical Sciences ,Biological Psychology ,Clinical Sciences ,Neurosciences ,Psychology ,Substance Misuse ,Alcoholism ,Alcohol Use and Health ,Biotechnology ,Genetics ,Human Genome ,Good Health and Well Being ,Black or African American ,Alcohol Drinking ,Alcoholism ,Genome-Wide Association Study ,Humans ,Risk Factors ,Public Health and Health Services ,Clinical sciences ,Biological psychology - Abstract
Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E-05 to 6.27E-03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E-03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32-2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.
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- 2022
15. Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts
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Mallard, Travis T, Savage, Jeanne E, Johnson, Emma C, Huang, Yuye, Edwards, Alexis C, Hottenga, Jouke J, Grotzinger, Andrew D, Gustavson, Daniel E, Jennings, Mariela V, Anokhin, Andrey, Dick, Danielle M, Edenberg, Howard J, Kramer, John R, Lai, Dongbing, Meyers, Jacquelyn L, Pandey, Ashwini K, Harden, Kathryn Paige, Nivard, Michel G, de Geus, Eco JC, Boomsma, Dorret I, Agrawal, Arpana, Davis, Lea K, Clarke, Toni-Kim, Palmer, Abraham A, and Sanchez-Roige, Sandra
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Mental Health ,Alcoholism ,Alcohol Use and Health ,Substance Misuse ,Brain Disorders ,Human Genome ,Prevention ,Genetics ,Cardiovascular ,Oral and gastrointestinal ,Mental health ,Good Health and Well Being ,Alcohol Drinking ,Alcoholism ,Genome-Wide Association Study ,Humans ,ALSPAC ,Alcohol ,Alcohol Consumption ,GWAS ,Genomic Structural Equation Modeling ,Substance-Related and Addictive Disorders ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Clinical sciences ,Clinical and health psychology - Abstract
ObjectiveGenome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT.MethodsTo explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases.ResultsThe authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health.ConclusionsThis work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.
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- 2022
16. Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use
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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, Pandey, Gayathri, Plawecki, Martin H, Sanchez-Roige, Sandra, Waldman, Irwin, Palmer, Abraham A, and Dick, Danielle M
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Biomedical and Clinical Sciences ,Health Sciences ,Psychology ,Pediatric Research Initiative ,Substance Misuse ,Behavioral and Social Science ,Genetics ,Prevention ,Pediatric ,Basic Behavioral and Social Science ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adolescent ,Adolescent Behavior ,Child ,Humans ,Longitudinal Studies ,Multifactorial Inheritance ,Parenting ,Parents ,Peer Group ,Risk Factors ,Substance-Related Disorders ,Adolescent externalizing ,Polygenic score ,Gene-environment interplay ,Peers ,Externalizing Consortium ,Gene–environment interplay ,Zoology ,Neurosciences ,Genetics & Heredity ,Biomedical and clinical sciences ,Health sciences - Abstract
Genetic 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.
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- 2021
17. Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease
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Lai, Dongbing, Alipanahi, Babak, Fontanillas, Pierre, Schwantes‐An, Tae‐Hwi, Aasly, Jan, Alcalay, Roy N, Beecham, Gary W, Berg, Daniela, Bressman, Susan, Brice, Alexis, Brockman, Kathrin, Clark, Lorraine, Cookson, Mark, Das, Sayantan, Van Deerlin, Vivianna, Follett, Jordan, Farrer, Matthew J, Trinh, Joanne, Gasser, Thomas, Goldwurm, Stefano, Gustavsson, Emil, Klein, Christine, Lang, Anthony E, Langston, J William, Latourelle, Jeanne, Lynch, Timothy, Marder, Karen, Marras, Connie, Martin, Eden R, McLean, Cory Y, Mejia‐Santana, Helen, Molho, Eric, Myers, Richard H, Nuytemans, Karen, Ozelius, Laurie, Payami, Haydeh, Raymond, Deborah, Rogaeva, Ekaterina, Rogers, Michael P, Ross, Owen A, Samii, Ali, Saunders‐Pullman, Rachel, Schüle, Birgitt, Schulte, Claudia, Scott, William K, Tanner, Caroline, Tolosa, Eduardo, Tomkins, James E, Vilas, Dolores, Trojanowski, John Q, Team, The 23andMe Research, Uitti, Ryan, Vance, Jeffery M, Visanji, Naomi P, Wszolek, Zbigniew K, Zabetian, Cyrus P, Mirelman, Anat, Giladi, Nir, Urtreger, Avi Orr, Cannon, Paul, Fiske, Brian, and Foroud, Tatiana
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Aging ,Genetics ,Brain Disorders ,Prevention ,Parkinson's Disease ,Neurodegenerative ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Aged ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Male ,Middle Aged ,Mutation ,Parkinson Disease ,Penetrance ,23andMe Research Team ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
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- 2021
18. Integration of evidence across human and model organism studies: A meeting report
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Palmer, Rohan HC, Johnson, Emma C, Won, Hyejung, Polimanti, Renato, Kapoor, Manav, Chitre, Apurva, Bogue, Molly A, Benca‐Bachman, Chelsie E, Parker, Clarissa C, Verma, Anurag, Reynolds, Timothy, Ernst, Jason, Bray, Michael, Bin Kwon, Soo, 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, and Williams, Robert W
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Human Genome ,Substance Misuse ,Networking and Information Technology R&D (NITRD) ,Brain Disorders ,Drug Abuse (NIDA only) ,Generic health relevance ,Good Health and Well Being ,cross-species ,data integration ,drug abuse ,genomics ,GWAS ,model organisms ,multi-omic ,substance use disorders ,working group ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Neurosciences - Abstract
The 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.
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- 2021
19. Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples
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Johnson, Emma C, Sanchez-Roige, Sandra, Acion, Laura, Adams, Mark J, Bucholz, Kathleen K, Chan, Grace, Chao, Michael J, Chorlian, David B, Dick, Danielle M, Edenberg, Howard J, Foroud, Tatiana, Hayward, Caroline, Heron, Jon, Hesselbrock, Victor, Hickman, Matthew, Kendler, Kenneth S, Kinreich, Sivan, Kramer, John, Kuo, Sally I-Chun, Kuperman, Samuel, Lai, Dongbing, McIntosh, Andrew M, Meyers, Jacquelyn L, Plawecki, Martin H, Porjesz, Bernice, Porteous, David, Schuckit, Marc A, Su, Jinni, Zang, Yong, Palmer, Abraham A, Agrawal, Arpana, Clarke, Toni-Kim, and Edwards, Alexis C
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Biological Psychology ,Biomedical and Clinical Sciences ,Psychology ,Neurosciences ,Brain Disorders ,Clinical Research ,Genetics ,Underage Drinking ,Substance Misuse ,Pediatric ,Alcoholism ,Alcohol Use and Health ,Good Health and Well Being ,Alcohol Drinking ,Alcoholism ,Cohort Studies ,Genome-Wide Association Study ,Humans ,Longitudinal Studies ,Phenotype ,Scotland ,Alcohol consumption ,alcohol dependence ,alcohol use disorder ,AUDIT ,genetics ,GWAS ,polygenic risk score ,Public Health and Health Services ,Psychiatry ,Clinical sciences ,Biological psychology ,Clinical and health psychology - Abstract
BackgroundStudies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.MethodsWe examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.ResultsIn COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16).ConclusionsAUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
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- 2021
20. Genome‐wide admixture mapping of DSM‐IV alcohol dependence, criterion count, and the self‐rating of the effects of ethanol in African American populations
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Lai, Dongbing, Kapoor, Manav, Wetherill, Leah, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Chao, Michael, Almasy, Laura, Bucholz, Kathleen, Hart, Ronald P, Kamarajan, Chella, Meyers, Jacquelyn L, Nurnberger, John I, Tischfield, Jay, Edenberg, Howard J, Schuckit, Marc, Goate, Alison, Scott, Denise M, Porjesz, Bernice, Agrawal, Arpana, and Foroud, Tatiana
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Pharmacology and Pharmaceutical Sciences ,Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Brain Disorders ,Human Genome ,Substance Misuse ,Alcoholism ,Alcohol Use and Health ,Good Health and Well Being ,Black or African American ,Alcoholism ,Case-Control Studies ,Diagnostic and Statistical Manual of Mental Disorders ,Ethanol ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Polymorphism ,Single Nucleotide ,Retrospective Studies ,Self Report ,White People ,admixture mapping ,African American ,criterion count ,DSM-IV alcohol dependence ,response to ethanol ,Clinical Sciences ,Neurosciences ,Clinical sciences - Abstract
African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations.
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- 2021
21. A large-scale genome-wide association study meta-analysis of cannabis use disorder.
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Johnson, Emma C, Demontis, Ditte, Thorgeirsson, Thorgeir E, Walters, Raymond K, Polimanti, Renato, Hatoum, Alexander S, Sanchez-Roige, Sandra, Paul, Sarah E, Wendt, Frank R, Clarke, Toni-Kim, Lai, Dongbing, Reginsson, Gunnar W, Zhou, Hang, He, June, Baranger, David AA, Gudbjartsson, Daniel F, Wedow, Robbee, Adkins, Daniel E, Adkins, Amy E, Alexander, Jeffry, Bacanu, Silviu-Alin, Bigdeli, Tim B, Boden, Joseph, Brown, Sandra A, Bucholz, Kathleen K, Bybjerg-Grauholm, Jonas, Corley, Robin P, Degenhardt, Louisa, Dick, Danielle M, Domingue, Benjamin W, Fox, Louis, Goate, Alison M, Gordon, Scott D, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Hickie, Ian B, Hougaard, David M, Krauter, Kenneth, Lind, Penelope A, McClintick, Jeanette N, McQueen, Matthew B, Meyers, Jacquelyn L, Montgomery, Grant W, Mors, Ole, Mortensen, Preben B, Nordentoft, Merete, Pearson, John F, Peterson, Roseann E, Reynolds, Maureen D, Rice, John P, Runarsdottir, Valgerdur, Saccone, Nancy L, Sherva, Richard, Silberg, Judy L, Tarter, Ralph E, Tyrfingsson, Thorarinn, Wall, Tamara L, Webb, Bradley T, Werge, Thomas, Wetherill, Leah, Wright, Margaret J, Zellers, Stephanie, Adams, Mark J, Bierut, Laura J, Boardman, Jason D, Copeland, William E, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Grucza, Richard A, Harris, Kathleen Mullan, Heath, Andrew C, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Horwood, John, Iacono, William G, Johnson, Eric O, Kendler, Kenneth S, Kennedy, Martin A, Kranzler, Henry R, Madden, Pamela AF, Maes, Hermine H, Maher, Brion S, Martin, Nicholas G, McGue, Matthew, McIntosh, Andrew M, Medland, Sarah E, Nelson, Elliot C, Porjesz, Bernice, Riley, Brien P, Stallings, Michael C, Vanyukov, Michael M, Vrieze, Scott, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Davis, Lea K, Bogdan, Ryan, Gelernter, Joel, and Edenberg, Howard J
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Psychiatric Genomics Consortium Substance Use Disorders Workgroup ,Humans ,Marijuana Abuse ,Risk ,Polymorphism ,Single Nucleotide ,Genome-Wide Association Study ,Polymorphism ,Single Nucleotide ,Clinical Sciences ,Public Health and Health Services ,Psychology - Abstract
BackgroundVariation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.MethodsTo conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.FindingsWe identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.InterpretationThese findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.FundingNational Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
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- 2020
22. Genomewide Meta‐Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent‐Induced Sensory Peripheral Neuropathy
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Chua, Katherina C, Xiong, Chenling, Ho, Carol, Mushiroda, Taisei, Jiang, Chen, Mulkey, Flora, Lai, Dongbing, Schneider, Bryan P, Rashkin, Sara R, Witte, John S, Friedman, Paula N, Ratain, Mark J, McLeod, Howard L, Rugo, Hope S, Shulman, Lawrence N, Kubo, Michiaki, Owzar, Kouros, and Kroetz, Deanna L
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Prevention ,Human Genome ,Peripheral Neuropathy ,Cancer ,Neurodegenerative ,Neurosciences ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Adult ,Aged ,Cells ,Cultured ,Female ,Genome-Wide Association Study ,Humans ,Male ,Middle Aged ,Neurites ,Paclitaxel ,Peripheral Nervous System Diseases ,Pharmacogenetics ,Pharmacogenomic Variants ,Polymorphism ,Single Nucleotide ,Randomized Controlled Trials as Topic ,Risk Assessment ,Risk Factors ,Sphingosine-1-Phosphate Receptors ,Tubulin Modulators ,Young Adult ,Pharmacology and Pharmaceutical Sciences ,Pharmacology & Pharmacy ,Pharmacology and pharmaceutical sciences - Abstract
Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genomewide association studies (GWAS) from two clinical cohorts treated with MTAs (Cancer and Leukemia Group B (CALGB) 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1 ; e.g., rs74497159, βCALGB 40101 per allele log hazard ratio (95% confidence interval (CI)) = 0.591 (0.254-0.928), βCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334-1.053); PMETA = 3.62 × 10-7 ) were the most highly ranked associations based on P values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in induced pluripotent stem cell-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.
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- 2020
23. Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium
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Polimanti, Renato, Walters, Raymond K, Johnson, Emma C, McClintick, Jeanette N, Adkins, Amy E, Adkins, Daniel E, Bacanu, Silviu-Alin, Bierut, Laura J, Bigdeli, Tim B, Brown, Sandra, Bucholz, Kathleen K, Copeland, William E, Costello, E Jane, Degenhardt, Louisa, Farrer, Lindsay A, Foroud, Tatiana M, Fox, Louis, Goate, Alison M, Grucza, Richard, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Heath, Andrew C, Hewitt, John K, Hopfer, Christian J, Johnson, Eric O, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lai, Dongbing, Madden, Pamela AF, Martin, Nicholas G, Maes, Hermine H, Nelson, Elliot C, Peterson, Roseann E, Porjesz, Bernice, Riley, Brien P, Saccone, Nancy, Stallings, Michael, Wall, Tamara L, Webb, Bradley T, Wetherill, Leah, Edenberg, Howard J, Agrawal, Arpana, and Gelernter, Joel
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Drug Abuse (NIDA only) ,Substance Misuse ,Neurosciences ,Brain Disorders ,Human Genome ,Genetics ,Mental Health ,Aetiology ,2.1 Biological and endogenous factors ,Mental health ,Good Health and Well Being ,Analgesics ,Opioid ,Behavior ,Addictive ,Female ,Genetic Predisposition to Disease ,Genetic Variation ,Genome ,Human ,Genome-Wide Association Study ,Genomics ,Humans ,Male ,Multifactorial Inheritance ,Opioid-Related Disorders ,Psychiatric Genomics Consortium Substance Use Disorders Workgroup ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Clinical sciences ,Biological psychology ,Clinical and health psychology - Abstract
To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.
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- 2020
24. Genome‐wide association studies of the self‐rating of effects of ethanol (SRE)
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Lai, Dongbing, Wetherill, Leah, Kapoor, Manav, Johnson, Emma C, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Joslyn, Geoff, Rao, Xi, Liu, Yunlong, Farris, Sean, Mayfield, R Dayne, Dick, Danielle, Hesselbrock, Victor, Kramer, John, McCutcheon, Vivia V, Nurnberger, John, Tischfield, Jay, Goate, Alison, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, and Schuckit, Marc
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Biomedical and Clinical Sciences ,Biological Psychology ,Epidemiology ,Health Sciences ,Psychology ,Pharmacology and Pharmaceutical Sciences ,Pediatric ,Substance Misuse ,Alcoholism ,Alcohol Use and Health ,Prevention ,Human Genome ,Genetics ,Good Health and Well Being ,Black or African American ,Alcoholism ,Ethanol ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Retrospective Studies ,Self Report ,Surveys and Questionnaires ,White People ,genetic correlation ,genome-wide association study ,heritability ,polygenic risk score ,RNA expression ,self-rating of the effects of ethanol ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Substance Abuse ,Biomedical and clinical sciences ,Health sciences - Abstract
The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.
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- 2020
25. ERRATUM: Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans
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Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, and Agrawal, Arpana
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Good Health and Well Being ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Published
- 2019
26. Decoding the Role of Secondary Motor Cortex Neuronal Ensembles during Cocaine Self-Administration: Insights from Longitudinal in vivo Calcium Imaging via Miniscopes
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Chen, Yingying, primary, Fu, Haoying, additional, Korada, Amith, additional, Lange, Michal A., additional, Rayanki, Chandrashekar, additional, Montgomery, Joreylis M.F., additional, Lu, Tao, additional, Lai, Dongbing, additional, Fang, Shiaofen, additional, Guo, Changyong, additional, and Ma, Yao-Ying, additional
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- 2024
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27. Genome‐wide association studies of alcohol dependence, DSM‐IV criterion count and individual criteria
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Lai, Dongbing, Wetherill, Leah, Bertelsen, Sarah, Carey, Caitlin E, Kamarajan, Chella, Kapoor, Manav, Meyers, Jacquelyn L, Anokhin, Andrey P, Bennett, David A, Bucholz, Kathleen K, Chang, Katharine K, De Jager, Philip L, Dick, Danielle M, Hesselbrock, Victor, Kramer, John, Kuperman, Samuel, Nurnberger, John I, Raj, Towfique, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Hariri, Ahmad R, Edenberg, Howard J, Agrawal, Arpana, Bogdan, Ryan, Porjesz, Bernice, Goate, Alison M, and Foroud, Tatiana
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Biological Sciences ,Genetics ,Human Genome ,Brain Disorders ,Alcoholism ,Alcohol Use and Health ,Substance Misuse ,Neurosciences ,Good Health and Well Being ,Adolescent ,Adult ,Black or African American ,Alcohol Dehydrogenase ,Alcoholism ,Diagnostic and Statistical Manual of Mental Disorders ,Female ,Humans ,Male ,Polymorphism ,Single Nucleotide ,Reward ,Theta Rhythm ,Ventral Striatum ,White People ,alcohol dependence ,DSM-IV alcohol dependence criterion ,DSM-IV criterion count ,DSM-IV individual criteria ,event-related theta oscillations ,functional magnetic resonance imaging ,genome-wide association study ,item response analysis ,meta-analysis ,polygenic risk score ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P
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- 2019
28. Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans
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Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, and Agrawal, Arpana
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Pharmacology and Pharmaceutical Sciences ,Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Human Genome ,Prevention ,Alcoholism ,Alcohol Use and Health ,Substance Misuse ,Drug Abuse (NIDA only) ,Brain Disorders ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Black or African American ,Chromosomes ,Human ,Pair 13 ,Chromosomes ,Human ,Pair 3 ,Genetic Loci ,Humans ,Phenotype ,Polymorphism ,Single Nucleotide ,Reward ,Substance-Related Disorders ,Ventral Striatum ,White People ,African-American ,alcohol dependence ,drug dependence ,European-American ,fMRI ,genetics ,GWAS ,heritability ,neural reward ,ventral striatum ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P
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- 2019
29. The Genetic Relationship Between Alcohol Consumption and Aspects of Problem Drinking in an Ascertained Sample.
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Johnson, Emma C, St Pierre, Celine L, Meyers, Jacquelyn L, Aliev, Fazil, McCutcheon, Vivia V, Lai, Dongbing, Dick, Danielle M, Goate, Alison M, Kramer, John, Kuperman, Samuel, Nurnberger, John I, Schuckit, Marc A, Porjesz, Bernice, Edenberg, Howard J, Bucholz, Kathleen K, and Agrawal, Arpana
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Humans ,Alcohol-Related Disorders ,Ethanol ,Central Nervous System Depressants ,Multifactorial Inheritance ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Genome-Wide Association Study ,ADH1B ,Alcohol Consumption ,Alcohol Dependence ,Polygenic Risk ,ADH1B ,Substance Abuse ,Clinical Sciences ,Psychology ,Neurosciences - Abstract
BackgroundGenomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples.MethodsIn 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWAS of weekly alcohol consumption in the UK Biobank predicted variance in 6 alcohol-related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self-Rating of the Effects of Ethanol Questionnaire (SRE-T), DSM-IV alcohol dependence (DSM4AD), DSM-5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRS interacted with sex, age, or family history of alcoholism to predict alcohol-related outcomes. We performed mixed-effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD.ResultsPRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Δmarginal R2 = 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R2 = 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R2 = 0.49%), MAXD (Δmarginal R2 = 0.31%), and SRE-T (Δmarginal R2 = 0.22%). PRS were also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08e-5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRS continued to exert an independent effect for all 5 alcohol measures (Δmarginal R2 after controlling for ADH1B = 0.14 to 1.22%). Interactions between PRS and sex, age, or family history were nonsignificant.ConclusionsGenetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWAS that focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking.
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- 2019
30. Meta‐Analysis of Genetic Influences on Initial Alcohol Sensitivity
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Edwards, Alexis C, Deak, Joseph D, Gizer, Ian R, Lai, Dongbing, Chatzinakos, Chris, Wilhelmsen, Kirk P, Lindsay, Jonathan, Heron, Jon, Hickman, Matthew, Webb, Bradley T, Bacanu, Silviu‐Alin, Foroud, Tatiana M, Kendler, Kenneth S, Dick, Danielle M, and Schuckit, Marc A
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Biomedical and Clinical Sciences ,Biological Psychology ,Clinical and Health Psychology ,Clinical Sciences ,Psychology ,Alcoholism ,Alcohol Use and Health ,Substance Misuse ,Genetics ,Human Genome ,Mental Health ,Stroke ,Cardiovascular ,Cancer ,Good Health and Well Being ,Adolescent ,Alcohol Drinking ,Alcoholism ,Cohort Studies ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Longitudinal Studies ,Male ,Polymorphism ,Single Nucleotide ,Risk Factors ,Sex Factors ,United Kingdom ,Avon Longitudinal Study of Parents and Children ,Genome-Wide Association Studies ,Heritability ,Initial Alcohol Sensitivity ,Self-Rating of the Effects of Alcohol ,Neurosciences ,Substance Abuse ,Clinical sciences ,Biological psychology ,Clinical and health psychology - Abstract
BackgroundPrevious studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported.MethodsWe conducted a meta-analysis of 2 population-based genome-wide association studies of the Self-Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)-based heritability and conducted a series of secondary aggregate genetic analyses.ResultsNo individual locus reached genome-wide significance. Gene and set based analyses, both overall and using tissue-specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta-analysis of SNP-based heritability resulted in a modest estimate of hSNP2 = 0.19 (SE = 0.10), though this was driven by 1 sample (N = 3,683, hSNP2 = 0.36, SE = 0.14, p = 0.04). No significant genetic correlations with other relevant outcomes were observed.ConclusionsFindings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings.
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- 2018
31. Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders
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Walters, Raymond K, Polimanti, Renato, Johnson, Emma C, McClintick, Jeanette N, Adams, Mark J, Adkins, Amy E, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M, Bigdeli, Tim B, Chen, Li-Shiun, Clarke, Toni-Kim, Chou, Yi-Ling, Degenhardt, Franziska, Docherty, Anna R, Edwards, Alexis C, Fontanillas, Pierre, Foo, Jerome C, Fox, Louis, Frank, Josef, Giegling, Ina, Gordon, Scott, Hack, Laura M, Hartmann, Annette M, Hartz, Sarah M, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hodgkinson, Colin, Hoffmann, Per, Jan Hottenga, Jouke, Kennedy, Martin A, Alanne-Kinnunen, Mervi, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S, Mbarek, Hamdi, McIntosh, Andrew M, McQueen, Matthew B, Meyers, Jacquelyn L, Milaneschi, Yuri, Palviainen, Teemu, Pearson, John F, Peterson, Roseann E, Ripatti, Samuli, Ryu, Euijung, Saccone, Nancy L, Salvatore, Jessica E, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T, Wedow, Robbee, Wetherill, Leah, Wills, Amanda G, Boardman, Jason D, Chen, Danfeng, Choi, Doo-Sup, Copeland, William E, Culverhouse, Robert C, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W, Elson, Sarah L, Frye, Mark A, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D, Nurnberger, John I, Palotie, Aarno, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A, Soyka, Michael, Treutlein, Jens, Witt, Stephanie, and Wodarz, Norbert
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Alcoholism ,Alcohol Use and Health ,Neurosciences ,Brain Disorders ,Substance Misuse ,Mental Health ,Genetics ,Behavioral and Social Science ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Good Health and Well Being ,Alcoholism ,Alleles ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Mental Disorders ,Phenotype ,Polymorphism ,Single Nucleotide ,23andMe Research Team ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
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- 2018
32. High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk
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Porjesz, B., Hesselbrock, V., Foroud, T., Agrawal, A., Dick, D., Edenberg, H.J., Nurnberger, J., Jr., Liu, Y., Kuperman, S., Kramer, J., Meyers, J., Kamarajan, C., Pandey, A., Bierut, L., Rice, J., Bucholz, K., Schuckit, M., Tischfield, J., Brooks, A., Hart, R., Almasy, L., Salvatore, J., Goate, A., Kapoor, M., Slesinger, P., Scott, D., Bauer, L., Wetherill, L., Xuei, X., Lai, D., O’Connor, S., Plawecki, M., Zang, Y., Acion, L., Chan, G., Chorlian, D.B., Zhang, J., Kinreich, S., Pandey, G., Chao, M., Anokhin, A., McCutcheon, V., Saccone, S., Aliev, F., Barr, P., Chin, H., Parsian, A., Nurnberger, John I., Jr., Wang, Yumin, Zang, Yong, Lai, Dongbing, Wetherill, Leah, Edenberg, Howard J., Aliev, Fazil, Plawecki, Martin H., Chorlian, David, Chan, Grace, Bucholz, Kathleen, Bauer, Lance, Kamarajan, Chella, Salvatore, Jessica E., Kapoor, Manav, Hesselbrock, Victor, Dick, Danielle, Bierut, Laura, McCutcheon, Vivia, Meyers, Jacquelyn L., Porjesz, Bernice, Kramer, John, Kuperman, Samuel, Kinreich, Sivan, and Anokhin, Andrey P.
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- 2022
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33. Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond
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Gaddis, Nathan, Mathur, Ravi, Marks, Jesse, Zhou, Linran, Quach, Bryan, Waldrop, Alex, Levran, Orna, Agrawal, Arpana, Randesi, Matthew, Adelson, Miriam, Jeffries, Paul W., Martin, Nicholas G., Degenhardt, Louisa, Montgomery, Grant W., Wetherill, Leah, Lai, Dongbing, Bucholz, Kathleen, Foroud, Tatiana, Porjesz, Bernice, Runarsdottir, Valgerdur, Tyrfingsson, Thorarinn, Einarsson, Gudmundur, Gudbjartsson, Daniel F., Webb, Bradley Todd, Crist, Richard C., Kranzler, Henry R., Sherva, Richard, Zhou, Hang, Hulse, Gary, Wildenauer, Dieter, Kelty, Erin, Attia, John, Holliday, Elizabeth G., McEvoy, Mark, Scott, Rodney J., Schwab, Sibylle G., Maher, Brion S., Gruza, Richard, Kreek, Mary Jeanne, Nelson, Elliot C., Thorgeirsson, Thorgeir, Stefansson, Kari, Berrettini, Wade H., Gelernter, Joel, Edenberg, Howard J., Bierut, Laura, Hancock, Dana B., and Johnson, Eric Otto
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- 2022
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34. Identification of a common polymorphism in COQ8B acting as a modifier of thoracic aortic aneurysm severity
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Landis, Benjamin J., Lai, Dongbing, Guo, Dong-Chuan, Corvera, Joel S., Idrees, Muhammad T., Stadler, Henry W., Cuevas, Christian, Needler, Gavin U., Vujakovich, Courtney E., Milewicz, Dianna M., Hinton, Robert B., and Ware, Stephanie M.
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- 2022
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35. Functional Analysis of G6PD Variants Associated With Low G6PD Activity in the All of Us Research Program
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Powell, Nicholas R, primary, Geck, Renee C, additional, Lai, Dongbing, additional, Shugg, Tyler, additional, Skaar, Todd C, additional, and Dunham, Maitreya, additional
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- 2024
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36. Polygenic Risk for Alcohol Use Disorder Affects Cellular Responses to Ethanol Exposure in a Human Microglial Cell Model
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Li, Xindi, primary, Liu, Jiayi, additional, Boreland, Andrew J., additional, Kapadia, Sneha, additional, Zhang, Siwei, additional, Stillitano, Alessandro C., additional, Abbo, Yara, additional, Clark, Lorraine, additional, Lai, Dongbing, additional, Liu, Yunlong, additional, Barr, Peter B, additional, Meyers, Jacquelyn L., additional, Kamarajan, Chella, additional, Kuang, Weipeng, additional, Agrawal, Arpana, additional, Slesinger, Paul A., additional, Dick, Danielle, additional, Salvatore, Jessica, additional, Tischfield, Jay, additional, Duan, Jubao, additional, Edenberg, Howard J., additional, Kreimer, Anat, additional, Hart, Ronald P., additional, and Pang, Zhiping P., additional
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- 2024
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37. A genome-wide association study of interhemispheric theta EEG coherence: implications for neural connectivity and alcohol use behavior
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Meyers, Jacquelyn L., Zhang, Jian, Chorlian, David B., Pandey, Ashwini K., Kamarajan, Chella, Wang, Jen-Chyong, Wetherill, Leah, Lai, Dongbing, Chao, Michael, Chan, Grace, Kinreich, Sivan, Kapoor, Manav, Bertelsen, Sarah, McClintick, Jeanette, Bauer, Lance, Hesselbrock, Victor, Kuperman, Samuel, Kramer, John, Salvatore, Jessica E., Dick, Danielle M., Agrawal, Arpana, Foroud, Tatiana, Edenberg, Howard J., Goate, Alison, and Porjesz, Bernice
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- 2021
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38. Genetic Variants Associated with Circulating Parathyroid Hormone
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Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, and Kestenbaum, Bryan
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Biomedical and Clinical Sciences ,Clinical Sciences ,Human Genome ,Genetics ,Prevention ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Adult ,Aged ,Europe ,Female ,Genetic Variation ,Genome-Wide Association Study ,Humans ,Male ,Middle Aged ,Parathyroid Hormone ,Polymorphism ,Single Nucleotide ,genome-wide association study ,human genetics ,mineral metabolism ,parathyroid hormone ,Urology & Nephrology ,Clinical sciences - Abstract
Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
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- 2017
39. Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure
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Schneider, Bryan P, Shen, Fei, Gardner, Laura, Radovich, Milan, Li, Lang, Miller, Kathy D, Jiang, Guanglong, Lai, Dongbing, O'Neill, Anne, Sparano, Joseph A, Davidson, Nancy E, Cameron, David, Gradus-Pizlo, Irmina, Mastouri, Ronald A, Suter, Thomas M, Foroud, Tatiana, and Sledge, George W
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Clinical Research ,Cancer ,Breast Cancer ,Clinical Trials and Supportive Activities ,Genetics ,Heart Disease ,Cardiovascular ,Patient Safety ,Prevention ,Human Genome ,Aging ,Anthracyclines ,Antibiotics ,Antineoplastic ,Breast Neoplasms ,Case-Control Studies ,Clinical Trials ,Phase III as Topic ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Heart Failure ,Humans ,Phenotype ,Polymorphism ,Single Nucleotide ,Prognosis ,Reproducibility of Results ,Risk Assessment ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeAnthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline.Experimental designWe performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE.ResultsWhen evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value
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- 2017
40. Testing influences of APOE and BDNF genes and heart failure on cognitive function
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Jung, Miyeon, Apostolova, Liana G., Gao, Sujuan, Burney, Heather N., Lai, Dongbing, Foroud, Tatiana, Saykin, Andrew J., and Pressler, Susan J.
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- 2021
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41. A large-scale genome-wide association study meta-analysis of cannabis use disorder
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Walters, Raymond, Polimanti, Renato, Johnson, Emma, McClintick, Jeanette, Hatoum, Alexander, He, June, Wendt, Frank, Zhou, Hang, Adams, Mark, Adkins, Amy, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna, Bigdeli, Tim, Chen, Li-Shiun, Clarke, Toni-Kim, Chou, Yi-Ling, Degenhardt, Franziska, Docherty, Anna, Edwards, Alexis, Fontanillas, Pierre, Foo, Jerome, Fox, Louis, Frank, Josef, Giegling, Ina, Gordon, Scott, Hack, Laura, Hartmann, Annette, Hartz, Sarah, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hodgkinson, Colin, Hoffman, Per, Hottenga, Jouke, Kennedy, Martin, Alanne-Kinnunen, Mervi, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion, Mbarek, Hamdi, McIntosh, Andrew, McQueen, Matthew, Meyers, Jacquelyn, Milaneschi, Yuri, Palviainen, Teemu, Pearson, John, Peterson, Roseann, Ripatti, Samuli, Ryu, Euijung, Saccone, Nancy, Salvatore, Jessica, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley, Wedow, Robbee, Wetherill, Leah, Wills, Amanda, Boardman, Jason, Chen, Danfeng, Choi, Doo-Sup, Copeland, William, Culverhouse, Robert, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin, Elson, Sarah, Frye, Mark, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison, Nurnberger, John, Palotie, Aarno, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc, Soyka, Michael, Treutlein, Jens, Witt, Stephanie, Wodarz, Norbert, Zill, Peter, Adkins, Daniel, Boden, Joseph, Boomsma, Dorret, Bierut, Laura, Brown, Sandra, Bucholz, Kathleen, Cichon, Sven, Costello, E. Jane, de Wit, Harriet, Diazgranados, Nancy, Dick, Danielle, Eriksson, Johan, Farrer, Lindsay, Foroud, Tatiana, Gillespie, Nathan, Goate, Alison, Goldman, David, Grucza, Richard, Hancock, Dana, Harris, Kathleen Mullan, Heath, Andrew, Hesselbrock, Victor, Hewitt, John, Hopfer, Christian, Horwood, John, Iacono, William, Johnson, Eric, Kaprio, Jaakko, Karpyak, Victor, Kendler, Kenneth, Kranzler, Henry, Krauter, Kenneth, Lichtenstein, Paul, Lind, Penelope, McGue, Matt, MacKillop, James, Madden, Pamela, Maes, Hermine, Magnusson, Patrik, Martin, Nicholas, Medland, Sarah, Montgomery, Grant, Nelson, Elliot, Nöthen, Markus, Palmer, Abraham, Pederson, Nancy, Penninx, Brenda, Porjesz, Bernice, Rice, John, Rietschel, Marcella, Riley, Brien, Rose, Richard, Rujescu, Dan, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael, Tarter, Ralph, Vanyukov, Michael, Vrieze, Scott, Wall, Tamara, Whitfield, John, Zhao, Hongyu, Neale, Benjamin, Gelernter, Joel, Edenberg, Howard, Agrawal, Arpana, Johnson, Emma C, Demontis, Ditte, Thorgeirsson, Thorgeir E, Walters, Raymond K, Hatoum, Alexander S, Paul, Sarah E, Wendt, Frank R, Reginsson, Gunnar W, Baranger, David A A, Gudbjartsson, Daniel F, Adkins, Daniel E, Adkins, Amy E, Alexander, Jeffry, Bigdeli, Tim B, Brown, Sandra A, Bucholz, Kathleen K, Bybjerg-Grauholm, Jonas, Corley, Robin P, Dick, Danielle M, Domingue, Benjamin W, Goate, Alison M, Gordon, Scott D, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Hickie, Ian B, Hougaard, David M, Lind, Penelope A, McClintick, Jeanette N, McQueen, Matthew B, Meyers, Jacquelyn L, Montgomery, Grant W, Mors, Ole, Mortensen, Preben B, Nordentoft, Merete, Pearson, John F, Peterson, Roseann E, Reynolds, Maureen D, Rice, John P, Runarsdottir, Valgerdur, Saccone, Nancy L, Silberg, Judy L, Tarter, Ralph E, Tyrfingsson, Thorarinn, Wall, Tamara L, Webb, Bradley T, Werge, Thomas, Wright, Margaret J, Zellers, Stephanie, Adams, Mark J, Bierut, Laura J, Boardman, Jason D, Copeland, William E, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Grucza, Richard A, Heath, Andrew C, Hewitt, John K, Hopfer, Christian J, Iacono, William G, Johnson, Eric O, Kendler, Kenneth S, Kennedy, Martin A, Kranzler, Henry R, Madden, Pamela A F, Maes, Hermine H, Maher, Brion S, Martin, Nicholas G, McGue, Matthew, McIntosh, Andrew M, Medland, Sarah E, Nelson, Elliot C, Riley, Brien P, Stallings, Michael C, Vanyukov, Michael M, Davis, Lea K, Bogdan, Ryan, Edenberg, Howard J, Stefansson, Kari, and Børglum, Anders D
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- 2020
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42. Epigenetic changes on rat chromosome 4 contribute to disparate alcohol drinking behavior in alcohol-preferring and -nonpreferring rats
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Spence, John Paul, Lai, Dongbing, Reiter, Jill L., Cao, Sha, Bell, Richard L., Williams, Kent E., and Liang, Tiebing
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- 2020
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43. Allele-specific expression and high-throughput reporter assay reveal functional genetic variants associated with alcohol use disorders
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Rao, Xi, Thapa, Kriti S., Chen, Andy B., Lin, Hai, Gao, Hongyu, Reiter, Jill L., Hargreaves, Katherine A., Ipe, Joseph, Lai, Dongbing, Xuei, Xiaoling, Wang, Yue, Gu, Hongmei, Kapoor, Manav, Farris, Sean P., Tischfield, Jay, Foroud, Tatiana, Goate, Alison M., Skaar, Todd C., Mayfield, R. Dayne, Edenberg, Howard J., and Liu, Yunlong
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- 2021
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44. Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension
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Powell, Nicholas R., primary, Shugg, Tyler, additional, Leighty, Jacob, additional, Martin, Matthew, additional, Kreutz, Rolf P., additional, Eadon, Michael T., additional, Lai, Dongbing, additional, Lu, Tao, additional, and Skaar, Todd C., additional
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- 2023
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45. Associations between alcohol use disorder polygenic score and remission in participants from high‐risk families and the Indiana Biobank
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Lai, Dongbing, primary, Kuo, Sally I‐Chun, additional, Wetherill, Leah, additional, Aliev, Fazil, additional, Zhang, Michael, additional, Marco, Abreu, additional, Schwantes‐An, Tae‐Hwi, additional, Dick, Danielle, additional, Francis, Meredith W., additional, Johnson, Emma C., additional, Kamarajan, Chella, additional, Kinreich, Sivan, additional, Kuperman, Samuel, additional, Meyers, Jacquelyn, additional, Nurnberger, John I., additional, Liu, Yunlong, additional, Edenberg, Howard J., additional, Porjesz, Bernice, additional, Agrawal, Arpana, additional, Foroud, Tatiana, additional, Schuckit, Marc, additional, Plawecki, Martin H., additional, Bucholz, Kathleen K., additional, and McCutcheon, Vivia V., additional
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- 2023
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46. Identifying genes associated with Alzheimer’s disease using gene‐based polygenic risk score
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Lai, Dongbing, primary, Zhang, Michael, additional, Li, Rudong, additional, Zhang, Chi, additional, Zhang, Pengyue, additional, Liu, Yunlong, additional, Gao, Sujuan, additional, and Foroud, Tatiana M., additional
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- 2023
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47. Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.
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Farlow, Janice L, Lin, Hai, Sauerbeck, Laura, Lai, Dongbing, Koller, Daniel L, Pugh, Elizabeth, Hetrick, Kurt, Ling, Hua, Kleinloog, Rachel, van der Vlies, Pieter, Deelen, Patrick, Swertz, Morris A, Verweij, Bon H, Regli, Luca, Rinkel, Gabriel JE, Ruigrok, Ynte M, Doheny, Kimberly, Liu, Yunlong, Broderick, Joseph, Foroud, Tatiana, and FIA Study Investigators
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FIA Study Investigators ,Humans ,Intracranial Aneurysm ,Genetic Predisposition to Disease ,Membrane Proteins ,Cohort Studies ,Chromosome Mapping ,Pedigree ,Sequence Analysis ,DNA ,Computational Biology ,Base Sequence ,Phenotype ,Molecular Sequence Data ,Genetic Variation ,Exome ,Sequence Analysis ,DNA ,General Science & Technology - Abstract
Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.
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- 2015
48. Genome-Wide Association Study of Intracranial Aneurysm Identifies a New Association on Chromosome 7
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Foroud, Tatiana, Lai, Dongbing, Koller, Daniel, Van't Hof, Femke, Kurki, Mitja I, Anderson, Craig S, Brown, Robert D, Connolly, Edward Sander, Eriksson, Johan G, Flaherty, Matthew, Fornage, Myriam, von Und Zu Fraunberg, Mikael, Gaál, Emília I, Laakso, Aki, Hernesniemi, Juha, Huston, John, Jääskeläinen, Juha E, Kiemeney, Lambertus A, Kivisaari, Riku, Kleindorfer, Dawn, Ko, Nerissa, Lehto, Hanna, Mackey, Jason, Meissner, Irene, Moomaw, Charles J, Mosley, Thomas H, Moskala, Marek, Niemelä, Mika, Palotie, Aarno, Pera, Joanna, Rinkel, Gabriel, Ripke, Stephan, Rouleau, Guy, Ruigrok, Ynte, Sauerbeck, Laura, Słowik, Agnieszka, Vermeulen, Sita H, Woo, Daniel, Worrall, Bradford B, and Broderick, Joseph
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Neurosciences ,Human Genome ,Stroke ,Genetics ,Brain Disorders ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Aged ,Chromosomes ,Human ,Pair 7 ,Cohort Studies ,Female ,Genome-Wide Association Study ,Humans ,Intracranial Aneurysm ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Whites ,chromosomes ,human ,pair 7 ,genome-wide association study ,intracranial aneurysm ,Familial Intracranial Aneurysm Study Investigators ,White People ,chromosomes ,human ,pair 7 ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Background and purposeCommon variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk.MethodsInitial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest.ResultsGenome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P
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- 2014
49. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
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Surendran, Praveen, Young, Robin, Barnes, Daniel R., Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Zhao, Wei, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J.M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrières, Jean, Kee, Frank, Kuulasmaa, Kari, Müller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, EPIC-CVD Consortium, Frossard, Philippe, Nordestgaard, Børge Grønne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Howson, Joanna M.M., Erzurumluoglu, A. Mesut, Jackson, Victoria E., Melbourne, Carl A., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian’an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renström, Frida, Hallmans, Göran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Völzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D.P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N.A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Understanding Society Scientific Group, Munroe, Patricia B., Jansson, Jan-Håkan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., Wain, Louise V., Tobin, Martin D., Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valérie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Bertelsen, Sarah, Chou, Yi-Ling, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Kardia, Sharon L.R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, McGue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Weir, David R., Kaprio, Jaakko, Abecasis, Gonçalo R., Liu, Dajiang J., and Vrieze, Scott
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- 2019
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50. Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension
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Powell, Nicholas R., Shugg, Tyler, Leighty, Jacob, Martin, Matthew, Kreutz, Rolf P., Eadon, Michael T., Lai, Dongbing, Lu, Tao, and Skaar, Todd C.
- Abstract
Hypertension (HTN) involves genetic variability in the renin‐angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen (AGT) messenger RNA (mRNA) is endogenously bound by miR‐122‐5p and rs699 A > G decreases reporter mRNA in the microRNA functional‐assay PASSPORT‐seq. The AGTpromoter variant rs5051 C > T is in linkage disequilibrium (LD) with rs699 A > G and increases AGTtranscription. The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGTby rs5051 C > T counterbalances AGTdecreased by rs699 A > G, and when these variants occur independently, it translates to HTN‐related phenotypes. We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis. In silico, rs699 A > G is predicted to increase miR‐122‐5p binding affinity by 3%. Mir‐eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA‐binding site in the AGTmRNA. Unexpectedly, rs699 A > G increases AGTmRNA in an AGT‐plasmid‐cDNA HepG2 expression model. Genotype‐Tissue Expression (GTEx) and UK Biobank analyses demonstrate liver AGTexpression and HTN phenotypes are not different when rs699 A > G occurs independently from rs5051 C > T. However, GTEx and the in vitro experiments suggest rs699 A > G confers cell‐type‐specific effects on AGTmRNA abundance, and suggest paracrine renal renin‐angiotensin‐system perturbations could mediate the rs699 A > G associations with HTN. We found that rs5051 C > T and rs699 A > G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a fourfold larger effect than in White participants. Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C > T or rs699 A > G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype. This study successfully tests the overarching hypothesis that rs699 A > G reduces angiotensinogen (AGT) expression independently from rs5051 C > T in the liver, demonstrating that these variants instead may be involved in influencing hypertension through nonliver‐mediated mechanisms.The results demonstrate that rs699 A > G and rs5051 C > T are associated with AGTmessenger RNA abundance in a cell‐type‐specific manner and have small but clinically meaningful associations (up to 2.7 mmHg) with blood pressure.The association between rs699 A > G and rs5051 C > T and increased AGTexpression in the kidney may have clinical significance since the kidney expresses the necessary enzymes to convert AGT to the prohypertensive angiotensin II as well as expressing the angiotensin II and pressor‐control receptors responsible for blood pressure‐raising effects.Further studies are warranted to investigate the potential for direct effects of rs699 A > G or rs5051 to the kidney and to determine if the reason for altered antihypertensive response in Black individuals might be due, in part, to the increased allele frequency of rs5051 C > T or rs699 A > G. This study successfully tests the overarching hypothesis that rs699 A > G reduces angiotensinogen (AGT) expression independently from rs5051 C > T in the liver, demonstrating that these variants instead may be involved in influencing hypertension through nonliver‐mediated mechanisms. The results demonstrate that rs699 A > G and rs5051 C > T are associated with AGTmessenger RNA abundance in a cell‐type‐specific manner and have small but clinically meaningful associations (up to 2.7 mmHg) with blood pressure. The association between rs699 A > G and rs5051 C > T and increased AGTexpression in the kidney may have clinical significance since the kidney expresses the necessary enzymes to convert AGT to the prohypertensive angiotensin II as well as expressing the angiotensin II and pressor‐control receptors responsible for blood pressure‐raising effects. Further studies are warranted to investigate the potential for direct effects of rs699 A > G or rs5051 to the kidney and to determine if the reason for altered antihypertensive response in Black individuals might be due, in part, to the increased allele frequency of rs5051 C > T or rs699 A > G.
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- 2024
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