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

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Authors: 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; Tischfield, Jay; Wang, Jen Chyong; Edenberg, Howard J; Goate, Alison; Foroud, Tatiana; Porjesz, Bernice
Year: 2017
Journal: International journal of psychophysiology : official journal of the International Organization of Psychophysiology
PMID: 28040410
DOI: 10.1016/j.ijpsycho.2016.12.008
PMCID: PMC5426060

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). The most significant SNP was rs2252790 (p<2.6×10; MAF=0.36; β=0.135). rs2252790 is an eQTL for ROS1 expressed most robustly in the temporal cortex (p=1.2×10) and for DSE/TSPYL4 expressed most robustly in the hippocampus (p=7.3×10; 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.

#	Section	Preview
40	Discussion	variation in ZEB2 may have broader neurobiological implications, beyond epilepsy. While no previous…
41	Discussion	Since the three genome-wide associated variants were located within an intron of DSE, this…
42	Discussion	This study also confirmed that several variants within GABRA2 were modestly (p<0.05) associated with…
43	Discussion — Limitations	Most notable is the relatively small sample size and related lack of statistical power to detect…
44	Discussion — Limitations	an effort to minimize age related differences in beta EEG genetic association findings. However,…
45	Discussion — Conclusions	To date, there have been relatively few genetic studies examining beta EEG, and only one finding…
46	Discussion — Conclusions	and CTBP2 were also associated with DSM-V AUD. Converging data from GWAS, gene expression, and…

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

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