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 PorjeszWilliam G. Lacono, Dorret I. Boomsma

*Corresponding author for this work

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

Funding

Personal funding: NWO 480-04-004, NWO/ SPI 56-464-14192, and NWO 911-09-032, NWO/MagW VENI-451-08-026, ERC- 230374; BBR Foundation (NARSAD), Grant/ Award Numbers: 21668, VU-USF 96/22, HFSP RG0154/1998-B, and KNAW PAH/ 6635; Australian Research Council, Grant/ Award Numbers: A79600334, A79906588, A79801419, DP0212016 and NHMRC 389891; Fellowship, Grant/Award Numbers: APP1103623 and NIH K01DA037914 National Institutes of Health (NIH), Grant/ Award Numbers: DA 05147, DA 36216, and DA 024417; COGA, Grant/Award Numbers: NIH NIAAA U10AA00840, NIH GEI U01HG004438, and HHSN268200782096C; Vrije Universiteit, Grant/Award Numbers: NOW/ZonMW 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463- 06-001, 451-04-034, 400-05-717, Addiction- 31160008, Middelgroot-911-09-032, Spino- zapremie 56-464-14192, BBMRI–NL, 184.021.007, NWO-Groot 480-15-001/674. ERC FP7/2007-2013, ENGAGE HEALTH-F4- 2007-201413, ERC Advanced 230374, Start- ing 284167, NIMH U24 MH068457-06, NIH R01D0042157-01A, MH081802, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995; ....................................................................................................................................................................................... This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. VC 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. This research was carried out under the auspices of the Enhancing Imaging Genetics through Meta-Analysis (ENIGMA) consortium. The ENIGMA-EEG Working Group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to Paul Thompson). The Collaborative Study of the Genetics of Alcoholism (COGA) continues to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and acknowledges all participating centers (see supplementary note). We gratefully acknowledge the following funding sources: University of Minnesota: Funding by National Institutes of Health (NIH) DA 05147, DA 36216, DA 024417. COGA: NIH NIAAA U10AA00840, NIH GEI U01HG004438, HHSN268200782096C. Vrije Universiteit: NOW/ZonMW 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56–464-14192, BBMRI–NL, 184.021.007, NWO-Groot 480-15-001/674. ERC FP7/2007–2013), ENGAGE HEALTH-F4–2007-201413, ERC Advanced 230374, Starting 284167), NIMH U24 MH068457-06, NIH R01D0042157-01A, MH081802, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995. Personal funding: NWO 480-04- 004, NWO/SPI 56–464-14192, and NWO 911-09- 032 to D.B., NWO/MagW VENI-451-08-026 to D.S.; ERC-230374 to D.B.; BBR Foundation (NARSAD) 21668 to D.S.; VU-USF 96/22 to D.B.; HFSP RG0154/1998-B to D.B. and E.d.G.; KNAW PAH/6635 to D.B.; Australian Research Council A79600334, A79906588, A79801419, DP0212016 to N.M. and M.W.; NHMRC 389891 to N.M.; Fellowship APP1103623 to S.M.; NIH K01DA037914 to J.L.M. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on October 20, 2016. See Supporting Information for a full acknowledgement. This research was carried out under the auspices of the Enhancing Imaging Genetics through Meta-Analysis (ENIGMA) consortium. The ENIGMA-EEG Working Group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to Paul Thompson). The Collaborative Study of the Genetics of Alcoholism (COGA) continues to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and acknowledges all participating centers (see supplementary note). We gratefully acknowledge the following funding sources: University of Minnesota: Funding by National Institutes of Health (NIH) DA 05147, DA 36216, DA 024417. COGA: NIH NIAAA U10AA00840, NIH GEI U01HG004438, HHSN268200782096C. Vrije Universiteit: NOW/ZonMW 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56–464-14192, BBMRI–NL, 184.021.007, NWO-Groot 480-15-001/674. ERC FP7/ 2007–2013), ENGAGE HEALTH-F4–2007-201413, ERC Advanced 230374, Starting 284167), NIMH U24 MH068457-06, NIH R01D0042157-01A, MH081802, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995. Personal funding: NWO 480-04-004, NWO/SPI 56–464-14192, and NWO 911-09-032 to D.B., NWO/MagW VENI-451-08-026 to D.S.; ERC-230374 to D.B.; BBR Foundation (NARSAD) 21668 to D.S.; VU-USF 96/22 to D.B.; HFSP RG0154/1998-B to D.B. and E.d.G.; KNAW PAH/6635 to D.B.; Australian Research Council A79600334, A79906588, A79801419, DP0212016 to N.M. and M.W.; NHMRC 389891 to N.M.; Fellowship APP1103623 to S.M.; NIH K01DA037914 to J.L.M. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on October 20, 2016. See Supporting Information for a full acknowledgement.

FundersFunder number
BBR Foundation
ENGAGEHEALTH-F4–2007-201413, 284167
NWO/MaGW
National Institutes of HealthDA 05147, DA 024417, DA 36216, ERC FP7/ 2007–2013
National Institute of Mental Health1RC2 MH089951, 1RC2 MH089995, VENI-451-08-026, R01 DK092127-04, NWO/SPI 56–464-14192, NWO 480-04-004, 911-09-032, U24 MH068457-06, MH081802, ERC-230374, R01D0042157-01A
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Cancer Institute
National Institute of Neurological Disorders and Stroke
National Institute of Child Health and Human DevelopmentR01HD042157
University of Minnesota
National Alliance for Research on Schizophrenia and DepressionHFSP RG0154/1998-B, KNAW PAH/6635, VU-USF 96/22, 21668
European Research Council230374
Australian Research CouncilDP0212016, A79600334, A79801419, NHMRC 389891, A79906588
National Health and Medical Research CouncilAPP1103623, K01DA037914, 389891
Koninklijke Nederlandse Akademie van WetenschappenPAH/ 6635
National Institute of Development Administration

    Keywords

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

    Cohort Studies

    • Netherlands Twin Register (NTR)

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