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
0	Introduction	The resting-state human electroencephalography (EEG) represents the ongoing oscillations of…
1	Introduction	et al., 2015). Further, coherence at the beta frequency may serve to establish transient…
2	Introduction	Despite the promise of the endo-phenotype concept however, the genetic complexity of resting-state…
3	Introduction	Previous studies report differences in the magnitude of beta EEG among individuals with alcohol use…
4	Introduction	in predicting relapse in abstinent individuals with AUD (Bauer, 2001; Saletu-Zyhlarz et al.). Since…
5	Introduction	2010b), ADHD (Choi et al., 2013), and internet addiction with comorbid depression (Lee et al.,…
6	Introduction	Resting state EEG is highly heritable (Malone et al., 2014; van Beijsterveldt et al., 1996), with…
7	Introduction	estimates provided by twin and family studies, there have been relatively few large (i.e.,…
8	Introduction	were genome-wide significant findings for other EEG parameters; an association was observed among…
9	Introduction	Given that beta EEG is highly heritable and has been found to be related to several externalizing…
10	Introduction	densely affected with AD. In an effort to move beyond genotype-phenotype association and further…
11	SAMPLE & METHODS — Sample	COGA recruited DSM-III-R and DSM-IV AD probands from inpatient and outpatient treatment facilities…
12	SAMPLE & METHODS — Sample	All COGA DNA samples were genotyped for a 96 SNP (single nucleotide polymorphism) array (Fluidigm…
13	SAMPLE & METHODS — EEG Recording & Processing	Prior to neurophysiological assessments, participants were required to have abstained from alcohol…
14	SAMPLE & METHODS — EEG Recording & Processing	Participants were seated comfortably in a dimly lit sound-attenuated temperature-regulated booth…
15	SAMPLE & METHODS — EEG Recording & Processing	50 Hz and digitized on a Concurrent (Atlanta, GA) 5550 computer at a sampling rate of 256 Hz or a…
16	SAMPLE & METHODS — EEG Recording & Processing	A continuous interval comprising 256 seconds of eyes-closed resting EEG data was analyzed. The raw…
17	SAMPLE & METHODS — EEG Recording & Processing	use of a Fourier transform. After windowing effects were minimized by application of a Hamming…
18	SAMPLE & METHODS — Genotyping, Imputation and Quality Review	Genotyping of 1,564 individuals from 117 EA families was performed at the Center for Inherited…
19	SAMPLE & METHODS — Genotyping, Imputation and Quality Review	needed, and then SNP genotypes were tested for Mendelian inconsistencies (Pedcheck; O’Connell &…

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

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