The heritability of alcoholism is 40-60% in both men and women, however, as in other complex psychiatric diseases, it has proved difficult to identify causative genes. Intermediate phenotypes are associated biological traits that may be influenced by variation at fewer genes and may mediate different aspects of the disease. The intermediate phenotypes we are studying include dimensional anxiety (harm avoidance (HA)), resting EEG phenotypes, event-related potentials (ERPs) and heart rate variability (HRV). We have three large intermediate phenotype datasets: 247 US Caucasians, 365 Plains American Indians with a high prevalence of alcoholism and 198 Southeastern American Indians with a low prevalence of alcoholism. We have identified an intermediate phenotype for alcoholism vulnerability, the low voltage alpha (LVA) EEG, a normal, traitlike heritable variant of the resting EEG, present in 7-14% of the population, in which the alpha rhythm is virtually absent. We have shown that LVA is associated with alcoholism, particularly when accompanied by anxiety disorders (Enoch et al 1995,1999). Moreover, we found that LVA individuals, irrespective of clinical state, had reduced auditory and visual P300 ERP amplitudes, further strengthening our argument for the association of LVA with alcoholism vulnerability (Enoch et al 2002). As expected, P300 amplitude was reduced in alcoholics, however, it was lowest in alcoholics with comorbid anxiety disorders (Enoch et al 2001). ? ? We are undertaking candidate gene analyses and have found that in both Caucasian and Plains Indian women, the low activity Met allele (and particularly the Met/Met homozygote) of the catechol-O-methyltransferase (COMT) Val158Met functional polymorphism is associated both with LVA and HA (Enoch et al, 2003). Moreover, in this tribe the COMT Met/Met genotype is protective against alcoholism and the Met158 allele is protective against smoking in women (Enoch et al, 2006). We have also found that LVA is associated with the DRD2 functional promoter polymorphism, -141CIns/Del. We have recently found associations between HA and BDNF functional variants (Jiang et al, 2005) and between alcoholism, mediated by HA, and an HNMT functional variant (Oroszi et al, 2005, Reuter et al, 2006). Recent analyses have shown that there may be two vulnerability factors for anxiety disorders with differing genetic susceptibility (HTTLPR, COMT Val158Met, BDNF Val66Met): (a) heightened attention (increased P300 amplitude) and better working memory with mildly elevated anxiety-neuroticism; a constellation that may be protective against other psychopathology, and (b) poorer attention and working memory with greater anxiety-neuroticism; a constellation that may also increase vulnerability to alcoholism and major depression (Enoch et al, submitted).? ? Our recent, high-density whole genome linkage scan in the Plains Indians has identified a convergence of resting EEG phenotypes (alpha and beta power at frontal and posterior leads) to a chromosome 5 region within which fewer than 20 first-line candidate genes are located. Preliminary analyses have shown an association of EEG power with corticotrophin releasing hormone binding protein (CRHBP), a gene that is implicated in stress and addiction. Further analyses are underway. ? ? Formerly titled """"""""Genetic studies of the electroencephalogram and event-related potentials"""""""" and """"""""Genetic studies of EEG and ERP traits related to alcoholism"""""""".

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Intramural Research (Z01)
Project #
1Z01AA000280-17
Application #
7317746
Study Section
(LNG)
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Jung, Y; Goldman, D (2018) Role of RNA modifications in brain and behavior. Genes Brain Behav 17:e12444
Reilly, Matthew T; Noronha, Antonio; Goldman, David et al. (2017) Genetic studies of alcohol dependence in the context of the addiction cycle. Neuropharmacology 122:3-21
Goldman, David (2014) The missing heritability of behavior: the search continues. Psychophysiology 51:1327-8
Zhou, Zhifeng; Enoch, Mary-Anne; Goldman, David (2014) Gene expression in the addicted brain. Int Rev Neurobiol 116:251-73
Ho, M K; Goldman, D; Heinz, A et al. (2010) Breaking barriers in the genomics and pharmacogenetics of drug addiction. Clin Pharmacol Ther 88:779-91
Araya, Ricardo; Hu, Xianzhang; Heron, Jon et al. (2009) Effects of stressful life events, maternal depression and 5-HTTLPR genotype on emotional symptoms in pre-adolescent children. Am J Med Genet B Neuropsychiatr Genet 150B:670-82
Enoch, Mary-Anne; White, Kenneth V; Waheed, Juwaria et al. (2008) Neurophysiological and genetic distinctions between pure and comorbid anxiety disorders. Depress Anxiety 25:383-92
Reuter, Martin; Jeste, Neelum; Klein, Thomas et al. (2007) Association of THR105Ile, a functional polymorphism of histamine N-methyltransferase (HNMT), with alcoholism in German Caucasians. Drug Alcohol Depend 87:69-75
Enoch, Mary-Anne; Shen, Pei-Hong; Xu, Ke et al. (2006) Using ancestry-informative markers to define populations and detect population stratification. J Psychopharmacol 20:19-26
Enoch, Mary-Anne; Waheed, Juwaria F; Harris, Claudia R et al. (2006) Sex differences in the influence of COMT Val158Met on alcoholism and smoking in plains American Indians. Alcohol Clin Exp Res 30:399-406

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