Browsing by Author "Nurnberger, John I., Jr."
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Item 21st-Century Genetics in Psychiatric Residency Training: How Do We Get There?(American Medical Association, 2019-03-01) Besterman, Aaron D.; Moreno-De-Luca, Daniel; Nurnberger, John I., Jr.; Psychiatry, School of MedicineItem A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency(Springer, 2024) Thomas, Nathaniel S.; Gillespie, Nathan A.; Chan, Grace; Edenberg, Howard J.; Kamarajan, Chella; I-Chun Kuo, Sally; Miller, Alex P.; Nurnberger, John I., Jr.; Tischfield, Jay; Dick, Danielle M.; Salvatore, Jessica E.; Medical and Molecular Genetics, School of MedicineContemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.Item A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks(Springer, 2013) Kapoor, Manav; Wang, Jen-Chyong; Wetherill, Leah; Le, Nhung; Bertelsen, Sarah; Hinrichs, Anthony L.; Budde, John; Agrawal, Arpana; Bucholz, Kathleen; Dick, Danielle; Harari, Oscar; Hesselbrock, Victor; Kramer, John; Nurnberger, John I., Jr.; Rice, John; Saccone, Nancy; Schuckit, Marc; Tischfield, Jay; Porjesz, Bernice; Edenberg, Howard J.; Bierut, Laura; Foroud, Tatiana; Goate, Alison; Medical and Molecular Genetics, School of MedicineMaximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10(-7)) and PLCL1 genes (p = 4.1 × 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10(-3), 3 × 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.Item Alcohol-Related, Drug-Related, and Non-Substance-Related Aggression: Three Facets of a Single Construct or Three Distinct Constructs?(Wiley, 2020-09) Chester, David S.; Bucholz, Kathleen K.; Chan, Grace; Kamarajan, Chella; Pandey, Ashwini K.; Wetherill, Leah; Kramer, John R.; Nurnberger, John I., Jr.; Salvatore, Jessica E.; Dick, Danielle M.; Medical and Molecular Genetics, School of MedicineBackground: Aggression often occurs alongside alcohol and drug misuse. However, it is not clear whether the latent and manifest relations among alcohol-related, drug-related, and non-substance-related aggression are separate manifestations of a single construct or instead are 3 distinct constructs. Methods: To examine these associations, we conducted a preregistered analysis of 13,490 participants in the Collaborative Study on the Genetics of Alcoholism. In a structured interview, participants reported their lifetime perpetration of these 3 aggression phenotypes. Results: The data were better fit by a model that treated these aggression phenotypes as 3 distinct latent factors, as compared to models in which the items all loaded onto 1 ("general") or 2 ("substance-related" and "non-substance-related") aggression factors. This 3-factor model fit better for men than women. Subsequent exploratory analyses then showed that among these 3 factors, alcohol-related aggression explained the variance of overall aggression better than the other 2 factors. Conclusions: Our findings suggest that these 3 forms of aggression are distinct phenotypes (especially among men). Yet, people's alcohol-related aggression can accurately characterize their overall aggressive tendencies across these domains. Future research will benefit from articulating the unique and shared pathways and risk factors underlying each of these facets of aggression.Item Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder research(Springer Nature, 2025) Cai, Na; Verhulst, Brad; Andreassen, Ole A.; Buitelaar, Jan; Edenberg, Howard J.; Hettema, John M.; Gandal, Michael; Grotzinger, Andrew; Jonas, Katherine; Lee, Phil; Mallard, Travis T.; Mattheisen, Manuel; Neale, Michael C.; Nurnberger, John I., Jr.; Peyrot, Wouter J.; Tucker-Drob, Elliot M.; Smoller, Jordan W.; Kendler, Kenneth S.; Biochemistry and Molecular Biology, School of MedicinePsychiatric disorders are highly comorbid, heritable, and genetically correlated [1-4]. The primary objective of cross-disorder psychiatric genetics research is to identify and characterize both the shared genetic factors that contribute to convergent disease etiologies and the unique genetic factors that distinguish between disorders [4, 5]. This information can illuminate the biological mechanisms underlying comorbid presentations of psychopathology, improve nosology and prediction of illness risk and trajectories, and aid the development of more effective and targeted interventions. In this review we discuss how estimates of comorbidity and identification of shared genetic loci between disorders can be influenced by how disorders are measured (phenotypic assessment) and the inclusion or exclusion criteria in individual genetic studies (sample ascertainment). Specifically, the depth of measurement, source of diagnosis, and time frame of disease trajectory have major implications for the clinical validity of the assessed phenotypes. Further, biases introduced in the ascertainment of both cases and controls can inflate or reduce estimates of genetic correlations. The impact of these design choices may have important implications for large meta-analyses of cohorts from diverse populations that use different forms of assessment and inclusion criteria, and subsequent cross-disorder analyses thereof. We review how assessment and ascertainment affect genetic findings in both univariate and multivariate analyses and conclude with recommendations for addressing them in future research.Item Binge and High-Intensity Drinking – Associations with Intravenous Alcohol Self-Administration and Underlying Risk Factors(Wiley, 2022) Plawecki, Martin H.; Boes, Julian; Wetherill, Leah; Kosobud, Ann E.K.; Stangl, Bethany L.; Ramchandani, Vijay A.; Zimmermann, Ulrich S.; Nurnberger, John I., Jr.; Schuckit, Marc; Edenberg, Howard J.; Pandey, Gayathri; Kamarajan, Chella; Porjesz, Bernice; Foroud, Tatiana; O’Connor, Sean; Psychiatry, School of MedicineSome styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders.Item A Biomarker Characterizing Neurodevelopment with applications in Autism(Nature Publishing Group, 2018-01-12) Wu, Di; José, Jorge V.; Nurnberger, John I., Jr.; Torres, Elizabeth B.; Medicine, School of MedicineDespite great advances in neuroscience and genetic studies, our understanding of neurodevelopmental disorders is still quite limited. An important reason is not having objective psychiatric clinical tests. Here we propose a quantitative neurodevelopment assessment by studying natural movement outputs. Movement is central to behaviors: It involves complex coordination, temporal alterations, and precise dynamic controls. We carefully analyzed the continuous movement output data, collected with high definition electromagnetic sensors at millisecond time scales. We unraveled new metrics containing striking physiological information that was unseen neither by using traditional motion assessments nor by naked eye observations. Our putative biomarker leads to precise individualized classifications. It illustrates clear differences between Autism Spectrum Disorder (ASD) subjects from mature typical developing (TD) individuals. It provides an ASD complementary quantitative classification, which closely agrees with the clinicaly assessed functioning levels in the spectrum. It also illustrates TD potential age-related neurodevelopmental trajectories. Applying our movement biomarker to the parents of the ASD individuals studied in the cohort also shows a novel potential familial signature ASD tie. This paper proposes a putative behavioral biomarker to characterize the level of neurodevelopment with high predicting power, as illustrated in ASD subjects as an example.Item Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression(Nature Publishing Group, 2018-01) Culverhouse, Robert C.; Saccone, Nancy L.; Horton, Amy C.; Ma, Yinjiao; Anstey, Kaarin J.; Banaschewski, Tobias; Burmeister, Margit; Cohen-Woods, Sarah; Etain, Bruno; Fisher, Helen L.; Goldman, Noreen; Guillaume, Sébastien; Horwood, John; Juhasz, Gabriella; Lester, Kathryn J.; Mandelli, Laura; Middeldorp, Christel M.; Olié, Emilie; Villafuerte, Sandra; Air, Tracy M.; Araya, Ricardo; Bowes, Lucy; Burns, Richard; Byrne, Enda M.; Coffey, Carolyn; Coventry, William L.; Gawronski, Katerina; Glei, Dana; Hatzimanolis, Alex; Hottenga, Jouke-Jan; Jaussent, Isabelle; Jawahar, Catharine; Jennen-Steinmetz, Christine; Kramer, John R.; Lajnef, Mohamed; Little, Keriann; zu Schwabedissen, Henriette Meyer; Nauck, Matthias; Nederhof, Esther; Petschner, Peter; Peyrot, Wouter J.; Schwahn, Christian; Sinnamon, Grant; Stacey, David; Tian, Yan; Toben, Catherine; Auwera, Sandra Van der; Wainwright, Nick; Wang, Jen-Chyong; Willemsen, Gonneke; Anderson, Ian M.; Arolt, Volker; Åslund, Cecilia; Bagdy, Gyorgy; Baune, Bernhard T.; Bellivier, Frank; Boomsma, Dorret I.; Courtet, Philippe; Dannlowski, Udo; de Geus, Eco J.C.; Deakin, John F. W.; Easteal, Simon; Eley, Thalia; Fergusson, David M.; Goate, Alison M.; Gonda, Xenia; Grabe, Hans J.; Holzman, Claudia; Johnson, Eric O.; Kennedy, Martin; Laucht, Manfred; Martin, Nicholas G.; Munafò, Marcus; Nilsson, Kent W.; Oldehinkel, Albertine J.; Olsson, Craig; Ormel, Johan; Otte, Christian; Patton, George C.; Penninx, Brenda W.J.H.; Ritchie, Karen; Sarchiapone, Marco; Scheid, JM; Serretti, Alessandro; Smit, Johannes H.; Stefanis, Nicholas C.; Surtees, Paul G.; Völzke, Henry; Weinstein, Maxine; Whooley, Mary; Nurnberger, John I., Jr.; Breslau, Naomi; Bierut, Laura J.; Psychiatry, School of MedicineThe hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations.Item Correction: Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder research(Springer Nature, 2025) Cai, Na; Verhulst, Brad; Andreassen, Ole A.; Buitelaar, Jan; Edenberg, Howard J.; Hettema, John M.; Gandal, Michael; Grotzinger, Andrew; Jonas, Katherine; Lee, Phil; Mallard, Travis T.; Mattheisen, Manuel; Neale, Michael C.; Nurnberger, John I., Jr.; Peyrot, Wouter J.; Tucker-Drob, Elliot M.; Smoller, Jordan W.; Kendler, Kenneth S.; Biochemistry and Molecular Biology, School of MedicineCorrection to: Molecular Psychiatry 10.1038/s41380-024-02878-x, published online 27 December 2024 In this article the author’s name Wouter J. Peyrot was incorrectly written as Wouter Peyrout. The original article has been corrected.Item Defining Suicidal Thought and Behavior Phenotypes for Genetic Studies(medRxiv, 2024-07-29) Monson, Eric T.; Colbert, Sarah M. C.; Andreassen, Ole A.; Ayinde, Olatunde O.; Bejan, Cosmin A.; Ceja, Zuriel; Coon, Hilary; DiBlasi, Emily; Izotova, Anastasia; Kaufman, Erin A.; Koromina, Maria; Myung, Woojae; Nurnberger, John I., Jr.; Serretti, Alessandro; Smoller, Jordan W.; Stein, Murray B.; Zai, Clement C.; Suicide Working Group of the Psychiatric Genomics Consortium; Aslan, Mihaela; Barr, Peter B.; Bigdeli, Tim B.; Harvey, Philip D.; Kimbrel, Nathan A.; Patel, Pujan R.; Cooperative Studies Program (CSP) #572; Ruderfer, Douglas; Docherty, Anna R.; Mullins, Niamh; Mann, J. John; Psychiatry, School of MedicineBackground: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.