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

Dirk J.A. Smit, Margaret J. Wright, Jacquelyn L. Meyers, Nicholas G. Martin, Yvonne Y.W. Ho, Stephen M. Malone, Jian Zhang, Scott J. Burwell, David B. Chorlian, Eco J.C. de Geus, Damiaan Denys, Narelle K. Hansell, Jouke Jan Hottenga, Matt McGue, Catharina E.M. van Beijsterveldt, Neda Jahanshad, Paul M. Thompson, Christopher D. Whelan, Sarah E. Medland, Bernice Porjesz & 2 others William G. Lacono, Dorret I. Boomsma

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1–3.75 Hz, theta 4–7.75 Hz, alpha 8–12.75 Hz, and beta 13–30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2—a known genetic marker for alcohol use disorder and epilepsy—significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q <.05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex–genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.

Original languageEnglish
Pages (from-to)4183-4195
Number of pages13
JournalHuman Brain Mapping
Volume39
Issue number11
Early online date26 Jun 2018
DOIs
Publication statusPublished - Nov 2018

Fingerprint

Genome-Wide Association Study
Psychiatry
Brain
Genes
Psychopathology
Single Nucleotide Polymorphism
Schizophrenia
Alcohols
Gene Expression
Interneurons
Automatic Data Processing
Bipolar Disorder
Genetic Markers
Electroencephalography
Biomarkers
History
Databases
Power (Psychology)

Keywords

  • brain expression pathway
  • electroencephalography (EEG)
  • endophenotype
  • genetic correlation
  • Genome-Wide Association Study (GWAS)
  • SNP heritability

Cite this

Smit, D. J. A., Wright, M. J., Meyers, J. L., Martin, N. G., Ho, Y. Y. W., Malone, S. M., ... Boomsma, D. I. (2018). Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity. Human Brain Mapping, 39(11), 4183-4195. https://doi.org/10.1002/hbm.24238
Smit, Dirk J.A. ; Wright, Margaret J. ; Meyers, Jacquelyn L. ; Martin, Nicholas G. ; Ho, Yvonne Y.W. ; Malone, Stephen M. ; Zhang, Jian ; Burwell, Scott J. ; Chorlian, David B. ; de Geus, Eco J.C. ; Denys, Damiaan ; Hansell, Narelle K. ; Hottenga, Jouke Jan ; McGue, Matt ; van Beijsterveldt, Catharina E.M. ; Jahanshad, Neda ; Thompson, Paul M. ; Whelan, Christopher D. ; Medland, Sarah E. ; Porjesz, Bernice ; Lacono, William G. ; Boomsma, Dorret I. / Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity. In: Human Brain Mapping. 2018 ; Vol. 39, No. 11. pp. 4183-4195.
@article{dbf3bc913473472d8c821ff14ab73e4d,
title = "Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity",
abstract = "Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1–3.75 Hz, theta 4–7.75 Hz, alpha 8–12.75 Hz, and beta 13–30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2—a known genetic marker for alcohol use disorder and epilepsy—significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q <.05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex–genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.",
keywords = "brain expression pathway, electroencephalography (EEG), endophenotype, genetic correlation, Genome-Wide Association Study (GWAS), SNP heritability",
author = "Smit, {Dirk J.A.} and Wright, {Margaret J.} and Meyers, {Jacquelyn L.} and Martin, {Nicholas G.} and Ho, {Yvonne Y.W.} and Malone, {Stephen M.} and Jian Zhang and Burwell, {Scott J.} and Chorlian, {David B.} and {de Geus}, {Eco J.C.} and Damiaan Denys and Hansell, {Narelle K.} and Hottenga, {Jouke Jan} and Matt McGue and {van Beijsterveldt}, {Catharina E.M.} and Neda Jahanshad and Thompson, {Paul M.} and Whelan, {Christopher D.} and Medland, {Sarah E.} and Bernice Porjesz and Lacono, {William G.} and Boomsma, {Dorret I.}",
note = "{\circledC} 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.",
year = "2018",
month = "11",
doi = "10.1002/hbm.24238",
language = "English",
volume = "39",
pages = "4183--4195",
journal = "Human Brain Mapping",
issn = "1065-9471",
publisher = "Wiley-Liss Inc.",
number = "11",

}

Smit, DJA, Wright, MJ, Meyers, JL, Martin, NG, Ho, YYW, Malone, SM, Zhang, J, Burwell, SJ, Chorlian, DB, de Geus, EJC, Denys, D, Hansell, NK, Hottenga, JJ, McGue, M, van Beijsterveldt, CEM, Jahanshad, N, Thompson, PM, Whelan, CD, Medland, SE, Porjesz, B, Lacono, WG & Boomsma, DI 2018, 'Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity' Human Brain Mapping, vol. 39, no. 11, pp. 4183-4195. https://doi.org/10.1002/hbm.24238

Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity. / Smit, Dirk J.A.; Wright, Margaret J.; Meyers, Jacquelyn L.; Martin, Nicholas G.; Ho, Yvonne Y.W.; Malone, Stephen M.; Zhang, Jian; Burwell, Scott J.; Chorlian, David B.; de Geus, Eco J.C.; Denys, Damiaan; Hansell, Narelle K.; Hottenga, Jouke Jan; McGue, Matt; van Beijsterveldt, Catharina E.M.; Jahanshad, Neda; Thompson, Paul M.; Whelan, Christopher D.; Medland, Sarah E.; Porjesz, Bernice; Lacono, William G.; Boomsma, Dorret I.

In: Human Brain Mapping, Vol. 39, No. 11, 11.2018, p. 4183-4195.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity

AU - Smit, Dirk J.A.

AU - Wright, Margaret J.

AU - Meyers, Jacquelyn L.

AU - Martin, Nicholas G.

AU - Ho, Yvonne Y.W.

AU - Malone, Stephen M.

AU - Zhang, Jian

AU - Burwell, Scott J.

AU - Chorlian, David B.

AU - de Geus, Eco J.C.

AU - Denys, Damiaan

AU - Hansell, Narelle K.

AU - Hottenga, Jouke Jan

AU - McGue, Matt

AU - van Beijsterveldt, Catharina E.M.

AU - Jahanshad, Neda

AU - Thompson, Paul M.

AU - Whelan, Christopher D.

AU - Medland, Sarah E.

AU - Porjesz, Bernice

AU - Lacono, William G.

AU - Boomsma, Dorret I.

N1 - © 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

PY - 2018/11

Y1 - 2018/11

N2 - Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1–3.75 Hz, theta 4–7.75 Hz, alpha 8–12.75 Hz, and beta 13–30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2—a known genetic marker for alcohol use disorder and epilepsy—significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q <.05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex–genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.

AB - Oscillatory activity is crucial for information processing in the brain, and has a long history as a biomarker for psychopathology. Variation in oscillatory activity is highly heritable, but current understanding of specific genetic influences remains limited. We performed the largest genome-wide association study to date of oscillatory power during eyes-closed resting electroencephalogram (EEG) across a range of frequencies (delta 1–3.75 Hz, theta 4–7.75 Hz, alpha 8–12.75 Hz, and beta 13–30 Hz) in 8,425 subjects. Additionally, we performed KGG positional gene-based analysis and brain-expression analyses. GABRA2—a known genetic marker for alcohol use disorder and epilepsy—significantly affected beta power, consistent with the known relation between GABAA interneuron activity and beta oscillations. Tissue-specific SNP-based imputation of gene-expression levels based on the GTEx database revealed that hippocampal GABRA2 expression may mediate this effect. Twenty-four genes at 3p21.1 were significant for alpha power (FDR q <.05). SNPs in this region were linked to expression of GLYCTK in hippocampal tissue, and GNL3 and ITIH4 in the frontal cortex–genes that were previously implicated in schizophrenia and bipolar disorder. In sum, we identified several novel genetic variants associated with oscillatory brain activity; furthermore, we replicated and advanced understanding of previously known genes associated with psychopathology (i.e., schizophrenia and alcohol use disorders). Importantly, these psychopathological liability genes affect brain functioning, linking the genes' expression to specific cortical/subcortical brain regions.

KW - brain expression pathway

KW - electroencephalography (EEG)

KW - endophenotype

KW - genetic correlation

KW - Genome-Wide Association Study (GWAS)

KW - SNP heritability

UR - http://www.scopus.com/inward/record.url?scp=85054451120&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054451120&partnerID=8YFLogxK

U2 - 10.1002/hbm.24238

DO - 10.1002/hbm.24238

M3 - Article

VL - 39

SP - 4183

EP - 4195

JO - Human Brain Mapping

JF - Human Brain Mapping

SN - 1065-9471

IS - 11

ER -