Browsing by Author "Manz, Niklas"

Now showing 1 - 6 of 6
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    A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53
    (Springer Nature, 2013) Wang, Jen-Chyong; Foroud, Tatiana; Hinrichs, Anthony L.; Le, Nhung X. H.; Bertelsen, Sarah; Budde, John P.; Harari, Oscar; Koller, Daniel L.; Wetherill, Leah; Agrawal, Arpana; Almasy, Laura; Brooks, Andrew I.; Bucholz, Kathleen; Dick, Danielle; Hesselbrock, Victor; Johnson, Eric O.; Kang, Sun; Kapoor, Manav; Kramer, John; Kuperman, Samuel; Madden, Pamela A. F.; Manz, Niklas; Martin, Nicholas G.; McClintick, Jeanette N.; Montgomery, Grant W.; Nurnberger, John I., Jr.; Rangaswamy, Madhavi; Rice, John; Schuckit, Marc; Tischfield, Jay A.; Whitfield, John B.; Xuei, Xiaoling; Porjesz, Bernice; Heath, Andrew C.; Edenberg, Howard J.; Bierut, Laura J.; Goate, Alison M.; Medical and Molecular Genetics, School of Medicine
    Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.
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    Family-based Genome-wide Association Study of Frontal Theta Oscillations Identifies Potassium Channel Gene KCNJ6
    (Wiley, 2012) Kang, Sun J.; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Wetherill, Leah; Hinrichs, Tony; Almasy, Laura; Brooks, Andy; Chorlian, David B.; Dick, Danielle; Hesselbrock, Victor; Kramer, John; Kuperman, Sam; Nurnberger, John, Jr.; Rice, John; Schuckit, Marc; Tischfield, Jay; Bierut, Laura J.; Edenberg, Howard J.; Goate, Alison; Foroud, Tatiana; Porjesz, Bernice; Psychiatry, School of Medicine
    Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634 583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 117 families densely affected by alcohol use disorders, recruited in the Collaborative Study on the Genetics of Alcoholism. Genome-wide significant association was found with several SNPs on chromosome 21 in KCNJ6 (a potassium inward rectifier channel; KIR3.2/GIRK2), with the most significant SNP at P = 4.7 × 10(-10)). The same SNPs were also associated with EROs from central and parietal electrodes, but with less significance, suggesting that the association is frontally focused. One imputed synonymous SNP in exon four, highly correlated with our top three SNPs, was significantly associated with the frontal theta ERO phenotype. These results suggest KCNJ6 or its product GIRK2 account for some of the variations in frontal theta band oscillations. GIRK2 receptor activation contributes to slow inhibitory postsynaptic potentials that modulate neuronal excitability, and therefore influence neuronal networks.
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    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 Medicine
    The 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.
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    Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults
    (Springer, 2013) Chorlian, David B.; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Dick, Danielle; Almasy, Laura; Bauer, Lance; Bucholz, Kathleen; Foroud, Tatiana; Hesselbrock, Victor; Kang, Sun J.; Kramer, John; Kuperman, Sam; Nurnberger, John, Jr.; Rice, John; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J.; Goate, Alison; Bierut, Laura; Porjesz, Bernice; Medical and Molecular Genetics, School of Medicine
    Discrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.
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    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 Medicine
    The 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.
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    A genome wide association study of fast beta EEG in families of European ancestry
    (Elsevier, 2017-05) Meyers, Jacquelyn L.; Zhang, Jian; Manz, Niklas; Rangaswamy, Madhavi; Kamarajan, Chella; Wetherill, Leah; Chorlian, David B.; Kang, Sun J.; Bauer, Lance; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John I., Jr.; Tischfield, Jay; Wang, Jen Chyong; Edenberg, Howard J.; Goate, Alison; Foroud, Tatiana; Porjesz, Bernice; Medical and Molecular Genetics, School of Medicine
    BACKGROUND: Differences in fast beta (20-28Hz) electroencephalogram (EEG) oscillatory activity distinguish some individuals with psychiatric and substance use disorders, suggesting that it may be a useful endophenotype for studying the genetics of disorders characterized by neural hyper-excitability. Despite the high heritability estimates provided by twin and family studies, there have been relatively few genetic studies of beta EEG, and to date only one genetic association finding has replicated (i.e., GABRA2). METHOD: In a sample of 1564 individuals from 117 families of European Ancestry (EA) drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Genome-Wide Association Study (GWAS) on resting-state fronto-central fast beta EEG power, adjusting regression models for family relatedness, age, sex, and ancestry. To further characterize genetic findings, we examined the functional and behavioral significance of GWAS findings. RESULTS: Three intronic variants located within DSE (dermatan sulfate epimerase) on 6q22 were associated with fast beta EEG at a genome wide significant level (p<5×10-8). The most significant SNP was rs2252790 (p<2.6×10-8; MAF=0.36; β=0.135). rs2252790 is an eQTL for ROS1 expressed most robustly in the temporal cortex (p=1.2×10-6) and for DSE/TSPYL4 expressed most robustly in the hippocampus (p=7.3×10-4; β=0.29). Previous studies have indicated that DSE is involved in a network of genes integral to membrane organization; gene-based tests indicated that several variants within this network (i.e., DSE, ZEB2, RND3, MCTP1, and CTBP2) were also associated with beta EEG (empirical p<0.05), and of these genes, ZEB2 and CTBP2 were associated with DSM-V Alcohol Use Disorder (AUD; empirical p<0.05).' DISCUSSION: In this sample of EA families enriched for AUDs, fast beta EEG is associated with variants within DSE on 6q22; the most significant SNP influences the mRNA expression of DSE and ROS1 in hippocampus and temporal cortex, brain regions important for beta EEG activity. Gene-based tests suggest evidence of association with related genes, ZEB2, RND3, MCTP1, CTBP2, and beta EEG. Converging data from GWAS, gene expression, and gene-networks presented in this study provide support for the role of genetic variants within DSE and related genes in neural hyperexcitability, and has highlighted two potential candidate genes for AUD and/or related neurological conditions: ZEB2 and CTBP2. However, results must be replicated in large, independent samples.