Browsing by Author "Edenberg, Howard"
Now showing 1 - 10 of 14
Results Per Page
Sort Options
Item Associations of parent–adolescent closeness with P3 amplitude, frontal theta, and binge drinking among offspring with high risk for alcohol use disorder(Wiley, 2023) Pandey, Gayathri; Kuo, Sally I-Chun; Horne-Osipenko, Kristina A.; Pandey, Ashwini K.; Kamarajan, Chella; Saenz de Viteri, Stacey; Kinreich, Sivan; Chorlian, David B.; Kuang, Weipeng; Stephenson, Mallory; Kramer, John; Anokhin, Andrey; Zang, Yong; Kuperman, Samuel; Hesselbrock, Victor; Schuckit, Marc; Dick, Danielle; Chan, Grace; McCutcheon, Vivia V.; Edenberg, Howard; Bucholz, Kathleen K.; Meyers, Jacquelyn L.; Porjesz, Bernice; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground: Parents impact their offspring's brain development, neurocognitive function, risk, and resilience for alcohol use disorder (AUD) via both genetic and socio-environmental factors. Individuals with AUD and their unaffected children manifest low parietal P3 amplitude and low frontal theta (FT) power, reflecting heritable neurocognitive deficits associated with AUD. Likewise, children who experience poor parenting tend to have atypical brain development and greater rates of alcohol problems. Conversely, positive parenting can be protective and critical for normative development of self-regulation, neurocognitive functioning and the neurobiological systems subserving them. Yet, the role of positive parenting in resiliency toward AUD is understudied and its association with neurocognitive functioning and behavioral vulnerability to AUD among high-risk offspring is less known. Using data from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1256, mean age [SD] = 19.25 [1.88]), we investigated the associations of closeness with mother and father during adolescence with offspring P3 amplitude, FT power, and binge drinking among high-risk offspring. Methods: Self-reported closeness with mother and father between ages 12 and 17 and binge drinking were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. P3 amplitude and FT power were assessed in response to target stimuli using a Visual Oddball Task. Results: Multivariate multiple regression analyses showed that closeness with father was associated with larger P3 amplitude (p = 0.002) and higher FT power (p = 0.01). Closeness with mother was associated with less binge drinking (p = 0.003). Among male offspring, closeness with father was associated with larger P3 amplitude, but among female offspring, closeness with mother was associated with less binge drinking. These associations remained statistically significant with father's and mothers' AUD symptoms, socioeconomic status, and offspring impulsivity in the model. Conclusions: Among high-risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences.Item Density and Dichotomous Family History Measures of Alcohol Use Disorder as Predictors of Behavioral and Neural Phenotypes: A Comparative Study Across Gender and Race/Ethnicity(Wiley, 2020-03) Pandey, Gayathri; Seay, Michael J.; Meyers, Jacquelyn L.; Chorlian, David B.; Pandey, Ashwini K.; Kamarajan, Chella; Ehrenberg, Morton; Pitti, Daniel; Kinreich, Sivan; de Viteri, Stacey Subbie-Saenz; Acion, Laura; Anokhin, Andrey; Bauer, Lance; Chan, Grace; Edenberg, Howard; Hesselbrock, Victor; Kuperman, Samuel; McCutcheon, Vivia V.; Bucholz, Kathleen K.; Schuckit, Marc; Porjesz, Bernice; Biochemistry and Molecular Biology, School of MedicineBackground: Family history (FH) is an important risk factor for the development of alcohol use disorder (AUD). A variety of dichotomous and density measures of FH have been used to predict alcohol outcomes; yet, a systematic comparison of these FH measures is lacking. We compared 4 density and 4 commonly used dichotomous FH measures and examined variations by gender and race/ethnicity in their associations with age of onset of regular drinking, parietal P3 amplitude to visual target, and likelihood of developing AUD. Methods: Data from the Collaborative Study on the Genetics of Alcoholism (COGA) were utilized to compute the density and dichotomous measures. Only subjects and their family members with DSM-5 AUD diagnostic information obtained through direct interviews using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) were included in the study. Area under receiver operating characteristic curves were used to compare the diagnostic accuracy of FH measures at classifying DSM-5 AUD diagnosis. Logistic and linear regression models were used to examine associations of FH measures with alcohol outcomes. Results: Density measures had greater diagnostic accuracy at classifying AUD diagnosis, whereas dichotomous measures presented diagnostic accuracy closer to random chance. Both dichotomous and density measures were significantly associated with likelihood of AUD, early onset of regular drinking, and low parietal P3 amplitude, but density measures presented consistently more robust associations. Further, variations in these associations were observed such that among males (vs. females) and Whites (vs. Blacks), associations of alcohol outcomes with density (vs. dichotomous) measures were greater in magnitude. Conclusions: Density (vs. dichotomous) measures seem to present more robust associations with alcohol outcomes. However, associations of dichotomous and density FH measures with different alcohol outcomes (behavioral vs. neural) varied across gender and race/ethnicity. These findings have great applicability for alcohol research examining FH of AUD.Item Detecting significant genotype-phenotype association rules in bipolar disorder: market research meets complex genetics(SpringerOpen, 2018-11-11) Breuer, René; Mattheisen, Manuel; Frank, Josef; Krumm, Bertram; Treutlein, Jens; Kassem, Layla; Strohmaier, Jana; Herms, Stefan; Mühleisen, Thomas W.; Degenhardt, Franziska; Cichon, Sven; Nöthen, Markus M.; Karypis, George; Kelsoe, John; Greenwood, Tiffany; Nievergelt, Caroline; Shilling, Paul; Shekhtman, Tatyana; Edenberg, Howard; Craig, David; Szelinger, Szabolcs; Nurnberger, John; Gershon, Elliot; Alliey‑Rodriguez, Ney; Zandi, Peter; Goes, Fernando; Schork, Nicholas; Smith, Erin; Koller, Daniel; Zhang, Peng; Badner, Judith; Berrettini, Wade; Bloss, Cinnamon; Byerley, William; Coryell, William; Foroud, Tatiana; Guo, Yirin; Hipolito, Maria; Keating, Brendan; Lawson, William; Liu, Chunyu; Mahon, Pamela; McInnis, Melvin; Murray, Sarah; Nwulia, Evaristus; Potash, James; Rice, John; Scheftner, William; Zöllner, Sebastian; McMahon, Francis J.; Rietschel, Marcella; Schulze, Thomas G.; Biochemistry and Molecular Biology, School of MedicineBACKGROUND: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. RESULTS: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. CONCLUSION: Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.Item Gender modulates the development of Theta Event Related Oscillations in Adolescents and Young Adults.(Elsevier, 2015-10-01) Chorlian, David B.; Rangaswamy, Madhavi; Manz, Niklas; Kamarajan, Chella; Pandey, Ashwini K.; Edenberg, Howard; Kuperman, Samuel; Porjesz, Bernice; Department of Biochemistry and Molecular Biology, IU School of MedicineThe developmental trajectories of theta band (4-7 Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. These tasks call upon attentional and working memory resources. Large differences in developmental rates between males and females were found; scalp location and task modality (visual or auditory) differences within males and females were small compared to gender differences. Trajectories of interregional and intermodal correlations between ERO power values exhibited increases with age in both genders, but showed a divergence in development between auditory and visual systems during ages 16 to 21. These results are consistent with previous electrophysiological and imaging studies and provide additional temporal detail about the development of neurophysiological indices of cognitive activity. Since measures of the P3 response has been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions.Item Gender-specific gene-environment interaction in alcohol dependence: the impact of daily life events and GABRA2(Springer, 2013-09) Perry, Brea L.; Pescosolido, Bernice A.; Bucholz, Kathleen; Edenberg, Howard; Kramer, John; Kuperman, Samuel; Schuckit, Marc Alan; Nurnberger Jr., John I.; Department of Biochemistry and Molecular Biology, IU School of MedicineGender-moderated gene-environment interactions are rarely explored, raising concerns about inaccurate specification of etiological models and inferential errors. The current study examined the influence of gender, negative and positive daily life events, and GABRA2 genotype (SNP rs279871) on alcohol dependence, testing two- and three-way interactions between these variables using multi-level regression models fit to data from 2,281 White participants in the Collaborative Study on the Genetics of Alcoholism. Significant direct effects of variables of interest were identified, as well as gender-specific moderation of genetic risk on this SNP by social experiences. Higher levels of positive life events were protective for men with the high-risk genotype, but not among men with the low-risk genotype or women, regardless of genotype. Our findings support the disinhibition theory of alcohol dependence, suggesting that gender differences in social norms, constraints and opportunities, and behavioral undercontrol may explain men and women's distinct patterns of association.Item Genes associated with alcohol outcomes show enrichment of effects with broad externalizing and impulsivity phenotypes in an independent sample(JSAD, 2015-01) Aliev, Fazil; Wetherill, Leah; Bierut, Laura; Bucholz, Kathleen K.; Edenberg, Howard; Foroud, Tatiana; Dick, Danielle M.; Department of Medical and Molecular Genetics, IU School of MedicineOBJECTIVE: The purpose of this study was to evaluate evidence for association with a panel of genes previously associated with alcohol-related traits in a new sample of adolescent and young adult individuals (N = 2,128; 51% female) collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA). We tested for association with phenotypes related to externalizing behavior, including diagnostic symptom counts for disorders on the externalizing spectrum (alcohol dependence, conduct disorder, adult antisocial personality disorder, and illicit drug dependence), and related behavioral/personality traits (Achenbach Externalizing, NEO Extraversion, NEO Conscientiousness, Zuckerman's Sensation Seeking, and the Barratt Impulsivity Scale) based on the substantial literature suggesting that these behaviors may be alternate manifestations of a shared genetic liability. METHOD: We tested for overall enrichment of the set of 215 genotyped single-nucleotide polymorphisms (SNPs) for each of the phenotypes. We conducted secondary analyses comparing results for sensation seeking with results for the other phenotypes. RESULTS: For all phenotypes, there was significant enrichment of association results (p < .05) compared with chance expectations. The greatest number of significant results was observed with the phenotype Sensation Seeking. Secondary analyses indicated that the number of SNPs yielding p < .05 with Sensation Seeking was significantly greater than that observed for each of the other phenotypes. CONCLUSIONS: We find evidence for enrichment of association results across a spectrum of externalizing phenotypes with a panel of candidate genes/SNPs selected based on previous suggestion of association with alcohol-related outcomes. In particular, we find significant enrichment of effects with sensation seeking, suggesting that this may be a particularly salient behavior associated with risk for alcohol-related problems.Item Genetic correlates of the development of theta event related oscillations in adolescents and young adults(Elsevier, 2017-05) Chorlian, David B.; Rangaswamy, Madhavi; Manz, Niklas; Meyers, Jacquelyn L.; Kang, Sun J.; Kamarajan, Chella; Pandey, Ashwini K.; Wang, Jen-Chyong; Wetherill, Leah; Edenberg, Howard; Porjesz, Bernice; Department of Biochemistry & Molecular Biology, IU School of MedicineThe developmental trajectories of theta band (4–7 Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. Associations between the theta EROs and genotypic variants of 4 KCNJ6 single nucleotide polymorphisms (SNPs) were found to vary with age, sex, scalp location, and task modality. Three of the four KCNJ6 SNPs studied here were found to be significantly associated with the same theta EROs in adults in a previous family genome wide association study. Since measures of the P3 response have been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of genetic effects on its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions.Item Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci(medRxiv, 2024-03-13) Strom, Nora I.; Gerring, Zachary F.; Galimberti, Marco; Yu, Dongmei; Halvorsen, Matthew W.; Abdellaoui, Abdel; Rodriguez-Fontenla, Cristina; Sealock, Julia M.; Bigdeli, Tim; Coleman, Jonathan R.; Mahjani, Behrang; Thorp, Jackson G.; Bey, Katharina; Burton, Christie L.; Luykx, Jurjen J.; Zai, Gwyneth; Alemany, Silvia; Andre, Christine; Askland, Kathleen D.; Banaj, Nerisa; Barlassina, Cristina; Becker Nissen, Judith; Bienvenu, O. Joseph; Black, Donald; Bloch, Michael H.; Boberg, Julia; Børte, Sigrid; Bosch, Rosa; Breen, Michael; Brennan, Brian P.; Brentani, Helena; Buxbaum, Joseph D.; Bybjerg-Grauholm, Jonas; Byrne, Enda M.; Cabana-Dominguez, Judith; Camarena, Beatriz; Camarena, Adrian; Cappi, Carolina; Carracedo, Angel; Casas, Miguel; Cavallini, Maria Cristina; Ciullo, Valentina; Cook, Edwin H.; Crosby, Jesse; Cullen, Bernadette A.; De Schipper, Elles J.; Delorme, Richard; Djurovic, Srdjan; Elias, Jason A.; Estivill, Xavier; Falkenstein, Martha J.; Fundin, Bengt T.; Garner, Lauryn; German, Chris; Gironda, Christina; Goes, Fernando S.; Grados, Marco A.; Grove, Jakob; Guo, Wei; Haavik, Jan; Hagen, Kristen; Harrington, Kelly; Havdahl, Alexandra; Höffler, Kira D.; Hounie, Ana G.; Hucks, Donald; Hultman, Christina; Janecka, Magdalena; Jenike, Eric; Karlsson, Elinor K.; Kelley, Kara; Klawohn, Julia; Krasnow, Janice E.; Krebs, Kristi; Lange, Christoph; Lanzagorta, Nuria; Levey, Daniel; Lindblad-Toh, Kerstin; Macciardi, Fabio; Maher, Brion; Mathes, Brittany; McArthur, Evonne; McGregor, Nathaniel; McLaughlin, Nicole C.; Meier, Sandra; Miguel, Euripedes C.; Mulhern, Maureen; Nestadt, Paul S.; Nurmi, Erika L.; O'Connell, Kevin S.; Osiecki, Lisa; Ousdal, Olga Therese; Palviainen, Teemu; Pedersen, Nancy L.; Piras, Fabrizio; Piras, Federica; Potluri, Sriramya; Rabionet, Raquel; Ramirez, Alfredo; Rauch, Scott; Reichenberg, Abraham; Riddle, Mark A.; Ripke, Stephan; Rosário, Maria C.; Sampaio, Aline S.; Schiele, Miriam A.; Skogholt, Anne Heidi; Sloofman, Laura G.; Smit, Jan; Soler, Artigas María; Thomas, Laurent F.; Tifft, Eric; Vallada, Homero; van Kirk, Nathanial; Veenstra-VanderWeele, Jeremy; Vulink, Nienke N.; Walker, Christopher P.; Wang, Ying; Wendland, Jens R.; Winsvold, Bendik S.; Yao, Yin; Zhou, Hang; 23andMe Research Team; VA Million Veteran Program; Estonian Biobank; CoGa research team; iPSYCH; HUNT research team; NORDiC research team; Agrawal, Arpana; Alonso, Pino; Berberich, Götz; Bucholz, Kathleen K.; Bulik, Cynthia M.; Cath, Danielle; Denys, Damiaan; Eapen, Valsamma; Edenberg, Howard; Falkai, Peter; Fernandez, Thomas V.; Fyer, Abby J.; Gaziano, J. M.; Geller, Dan A.; Grabe, Hans J.; Greenberg, Benjamin D.; Hanna, Gregory L.; Hickie, Ian B.; Hougaard, David M.; Kathmann, Norbert; Kennedy, James; Lai, Dongbing; Landén, Mikael; Le Hellard, Stéphanie; Leboyer, Marion; Lochner, Christine; McCracken, James T.; Medland, Sarah E.; Mortensen, Preben B.; Neale, Benjamin M.; Nicolini, Humberto; Nordentoft, Merete; Pato, Michele; Pato, Carlos; Pauls, David L.; Piacentini, John; Pittenger, Christopher; Posthuma, Danielle; Ramos-Quiroga, Josep Antoni; Rasmussen, Steven A.; Richter, Margaret A.; Rosenberg, David R.; Ruhrmann, Stephan; Samuels, Jack F.; Sandin, Sven; Sandor, Paul; Spalletta, Gianfranco; Stein, Dan J.; Stewart, S. Evelyn; Storch, Eric A.; Stranger, Barbara E.; Turiel, Maurizio; Werge, Thomas; Andreassen, Ole A.; Børglum, Anders D.; Walitza, Susanne; Hveem, Kristian; Hansen, Bjarne K.; Rück, Christian P.; Martin, Nicholas G.; Milani, Lili; Mors, Ole; Reichborn-Kjennerud, Ted; Ribasés, Marta; Kvale, Gerd; Mataix-Cols, David; Domschke, Katharina; Grünblatt, Edna; Wagner, Michael; Zwart, John-Anker; Breen, Gerome; Nestadt, Gerald; Kaprio, Jaakko; Arnold, Paul D.; Grice, Dorothy E.; Knowles, James A.; Ask, Helga; Verweij, Karin J.; Davis, Lea K.; Smit, Dirk J.; Crowley, James J.; Scharf, Jeremiah M.; Stein, Murray B.; Gelernter, Joel; Mathews, Carol A.; Derks, Eske M.; Mattheisen, Manuel; Biochemistry and Molecular Biology, School of MedicineObsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.Item Genome-wide meta-analyses of cross substance use disorders in European, African, and Latino ancestry populations(Research Square, 2024-07-16) Lai, Dongbing; Zhang, Michael; Green, Nick; Abreu, Marco; Schwantes-An, Tae-Hwi; Parker, Clarissa; Zhang, Shanshan; Jin, Fulai; Sun, Anna; Zhang, Pengyue; Edenberg, Howard; Liu, Yunlong; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineGenetic risks for substance use disorders (SUDs) are due to both SUD-specific and SUD-shared genes. We performed the largest multivariate analyses to date to search for SUD-shared genes using samples of European (EA), African (AA), and Latino (LA) ancestries. By focusing on variants having cross-SUD and cross-ancestry concordant effects, we identified 45 loci. Through gene-based analyses, gene mapping, and gene prioritization, we identified 250 SUD-shared genes. These genes are highly expressed in amygdala, cortex, hippocampus, hypothalamus, and thalamus, primarily in neuronal cells. Cross-SUD concordant variants explained ~ 50% of the heritability of each SUD in EA. The top 5% individuals having the highest polygenic scores were approximately twice as likely to have SUDs as others in EA and LA. Polygenic scores had higher predictability in females than in males in EA. Using real-world data, we identified five drugs targeting identified SUD-shared genes that may be repurposed to treat SUDs.Item Genome-wide parametric linkage analyses of 644 bipolar pedigrees suggest susceptibility loci at chromosomes 16 and 20(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2008-08) Ross, Jessica; Berrettini, Wade; Coryell, William; Gershon, Elliot S.; Badner, Judith A.; Kelsoe, John R.; McInnis, Melvin G.; McMahon, Francis J.; Murphy, Dennis L.; Nurnberger, John I.; Foroud, Tatiana; Rice, John P.; Scheftner, William B.; Zandi, Peter; Edenberg, Howard; Byerley, William; Department of Psychiatry, IU School of MedicineOBJECTIVE: Our aim is to map chromosomal regions that harbor loci that increase susceptibility to bipolar disorder. METHODS: We analyzed 644 bipolar families ascertained by the National Institute of Mental Health Human Genetics Initiative for bipolar disorder. The families have been genotyped with microsatellite loci spaced every approximately 10 cM or less across the genome. Earlier analyses of these pedigrees have been limited to nonparametric (model-free) methods and thus, information from unaffected subjects with genotypes was not considered. In this study, we used parametric analyses assuming dominant and recessive transmission and specifying a maximum penetrance of 70%, so that information from unaffecteds could be weighed in the linkage analyses. As in previous linkage analyses of these pedigrees, we analyzed three diagnostic categories: model 1 included only bipolar I and schizoaffective, bipolar cases (1565 patients of whom approximately 4% were schizoaffective, bipolar); model 2 included all individuals in model 1 plus bipolar II patients (1764 total individuals); and model 3 included all individuals in model 2 with the addition of patients with recurrent major depressive disorder (2046 total persons). RESULTS: Assuming dominant inheritance the highest genome-wide pair-wise logarithm of the odds (LOD) score was 3.2 with D16S749 using model 2 patients. Multipoint analyses of this region yielded a maximum LOD score of 4.91. Under recessive transmission a number of chromosome 20 markers were positive and multipoint analyses of the area gave a maximum LOD of 3.0 with model 2 cases. CONCLUSION: The chromosome 16p and 20 regions have been implicated by some studies and the data reported herein provide additional suggestive evidence of bipolar susceptibility genes in these regions.