A genome wide association study of fast beta EEG in families of European ancestry

Abstract

BACKGROUND Differences in fast beta (20–28 Hz) 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 1,564 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.

Multivariate Analyses Reveal Biological Components Related to Neuronal Signaling and Immunity Mediating Electroencephalograms Abnormalities in Alcohol‐Dependent Individuals from the Collaborative Study on the Genetics of Alcoholism Cohort

“…GWASs and quantitative trait loci mapping studies in COGA and other large‐scale alcoholism cohorts have identified numerous disease‐associated loci (Clarke et al., ; Meyers et al., ). The most‐replicated alcohol dependence–related genes include ADH1B ( in European and African‐ancestry subjects ) and ALDH2 ( in Asians ).…”

“…Electroencephalograms (EEG) are promising, noninvasive functional brain phenotypes used to study neurophysiological effects of chronic alcohol abuse and withdrawal, both at rest (resting EEG) and during cognitive paradigms (event‐related potentials and oscillations; Rangaswamy and Porjesz, ). Because resting EEG is relatively stable throughout healthy adult life and highly heritable (Tang et al., ), it is used to study chronic alcoholics and their offspring (Begleiter and Porjesz, ; Rangaswamy and Porjesz, ), including earlier linkage and association genetic studies (Edenberg et al., ), and more recently with genomewide association (GWA; Meyers et al., ; Smit et al., ).…”

Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity

“…Current sample sizes may be adequate to reveal significant individual genetic associations, pathways for the expression of psychiatric liability in the brain, and prove hopeful for future GWAS of additional EEG parameters. For example, two recently published GWASs of bipolar EEG from families of African and European ancestry reported genome-wide signal at 3q26 and 6q22, respectively 31,80…”

Human brain arousal in the resting state: a genome-wide association study

“…In addition, the power of the arousal-indicating EEG frequency bands was observed with heritabilities of 80% [29]. To date, there have been four GWAS on resting state EEG activity [29][30][31][32]. However, none has assessed arousal and its regulation.…”

“…Moreover, we conducted a GWAS catalog screening and queried our top hits in the Psychiatric Genomics Consortium data files. In addition, we derived candidate markers from the four GWAS on other resting EEG activity traits [29][30][31][32].…”