title: A genome wide association study of fast beta EEG in families of European ancestry.
abstract: 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).
  
  
  
  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.
  
  
  
  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).'
  
  
  
  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.
authors.affiliation: Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA. Electronic address: meyersjl@hbnl.downstate.edu.
authors.forename: Jacquelyn L
authors.initials: JL
authors.lastname: Meyers
authors.affiliation: Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA; Department of Physics, College of Wooster, Wooster, OH, USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Manz
authors.affiliation: Department of Psychology, Christ University, Bangalore, India.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Rangaswamy
authors.affiliation: Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Chella
authors.initials: C
authors.lastname: Kamarajan
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Wetherill
authors.affiliation: Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Chorlian
authors.affiliation: Albany Stratton VA Medical Center, Albany, NY, USA.
authors.forename: Sun J
authors.initials: SJ
authors.lastname: Kang
authors.affiliation: University of Connecticut School of Medicine, Farmington, CT, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Bauer
authors.affiliation: University of Connecticut School of Medicine, Farmington, CT, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Hesselbrock
authors.affiliation: Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kramer
authors.affiliation: Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Kuperman
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: John I
authors.initials: JI
authors.lastname: Nurnberger
authors.affiliation: Rutgers University, Piscataway, NJ, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Tischfield
authors.affiliation: Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
authors.forename: Jen Chyong
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.affiliation: Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.affiliation: Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Bernice
authors.initials: B
authors.lastname: Porjesz
mesh_terms: D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology*; D001611:Beta Rhythm / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000502:physiology; D004569:Electroencephalography; D005260:Female; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000378:metabolism; D044465:White People
chemical_list: D012333:RNA, Messenger
keywords: Electrophysiology; Endophenotype; Genome-Wide Association Study (GWAS); Resting EEG