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

Jacquelyn L. Meyers, Jian Zhang, Niklas Manz, Madhavi Rangaswamy, Chella Kamarajan, Leah Wetherill, David B. Chorlian, Sun J. Kang, Lance Bauer, Victor Hesselbrock, John Kramer, Samuel Kuperman, John Nurnberger, Jay Tischfield, Jen Chyong Wang, Howard Edenberg, Alison Goate, Tatiana Foroud, Bernice Porjesz

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 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 <5×10-8). 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.

Original languageEnglish (US)
JournalInternational Journal of Psychophysiology
DOIs
StateAccepted/In press - Sep 15 2015

Fingerprint

Racemases and Epimerases
Genome-Wide Association Study
Dermatan Sulfate
Electroencephalography
Genes
Gene Regulatory Networks
Temporal Lobe
Single Nucleotide Polymorphism
Hippocampus
Endophenotypes
Inborn Genetic Diseases
Twin Studies
Diagnostic and Statistical Manual of Mental Disorders
Alcoholism
Substance-Related Disorders
Psychiatry
Alcohols
Genome
Gene Expression
Messenger RNA

Keywords

  • Electrophysiology
  • Endophenotype
  • Genome-Wide Association Study (GWAS)
  • Resting EEG

ASJC Scopus subject areas

  • Neuroscience(all)
  • Neuropsychology and Physiological Psychology
  • Physiology (medical)

Cite this

Meyers, J. L., Zhang, J., Manz, N., Rangaswamy, M., Kamarajan, C., Wetherill, L., ... Porjesz, B. (Accepted/In press). A genome wide association study of fast beta EEG in families of European ancestry. International Journal of Psychophysiology. https://doi.org/10.1016/j.ijpsycho.2016.12.008

A genome wide association study of fast beta EEG in families of European ancestry. / 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; Tischfield, Jay; Wang, Jen Chyong; Edenberg, Howard; Goate, Alison; Foroud, Tatiana; Porjesz, Bernice.

In: International Journal of Psychophysiology, 15.09.2015.

Research output: Contribution to journalArticle

Meyers, JL, Zhang, J, Manz, N, Rangaswamy, M, Kamarajan, C, Wetherill, L, Chorlian, DB, Kang, SJ, Bauer, L, Hesselbrock, V, Kramer, J, Kuperman, S, Nurnberger, J, Tischfield, J, Wang, JC, Edenberg, H, Goate, A, Foroud, T & Porjesz, B 2015, 'A genome wide association study of fast beta EEG in families of European ancestry', International Journal of Psychophysiology. https://doi.org/10.1016/j.ijpsycho.2016.12.008
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 ; Tischfield, Jay ; Wang, Jen Chyong ; Edenberg, Howard ; Goate, Alison ; Foroud, Tatiana ; Porjesz, Bernice. / A genome wide association study of fast beta EEG in families of European ancestry. In: International Journal of Psychophysiology. 2015.
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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 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 <5×10-8). 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.",
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TY - JOUR

T1 - A genome wide association study of fast beta EEG in families of European ancestry

AU - Meyers, Jacquelyn L.

AU - Zhang, Jian

AU - Manz, Niklas

AU - Rangaswamy, Madhavi

AU - Kamarajan, Chella

AU - Wetherill, Leah

AU - Chorlian, David B.

AU - Kang, Sun J.

AU - Bauer, Lance

AU - Hesselbrock, Victor

AU - Kramer, John

AU - Kuperman, Samuel

AU - Nurnberger, John

AU - Tischfield, Jay

AU - Wang, Jen Chyong

AU - Edenberg, Howard

AU - Goate, Alison

AU - Foroud, Tatiana

AU - Porjesz, Bernice

PY - 2015/9/15

Y1 - 2015/9/15

N2 - 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 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 <5×10-8). 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.

AB - 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 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 <5×10-8). 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.

KW - Electrophysiology

KW - Endophenotype

KW - Genome-Wide Association Study (GWAS)

KW - Resting EEG

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