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; William G. Lacono; Dorret I. Boomsma

doi:10.1002/hbm.24238

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

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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 GABA_A 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 language	English (US)
Pages (from-to)	4183-4195
Number of pages	13
Journal	Human Brain Mapping
Volume	39
Issue number	11
DOIs	https://doi.org/10.1002/hbm.24238
State	Published - Nov 2018

Bibliographical note

Funding Information:
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

Funding Information:
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.

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/hbm.24238

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Smit, D. J. A., Wright, M. J., Meyers, J. L., Martin, N. G., Ho, Y. Y. W., Malone, S. M., Zhang, J., Burwell, S. J., Chorlian, D. B., de Geus, E. J. C., Denys, D., Hansell, N. K., Hottenga, J. J., McGue, M., van Beijsterveldt, C. E. M., Jahanshad, N., Thompson, P. M., Whelan, C. D., Medland, S. E., ... 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, 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

@article{bbafada5c467481799cc589523682ddf,

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

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 = "Funding Information: 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 Funding Information: 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. Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.",

year = "2018",

month = nov,

doi = "10.1002/hbm.24238",

language = "English (US)",

volume = "39",

pages = "4183--4195",

journal = "Human Brain Mapping",

issn = "1065-9471",

publisher = "Wiley-Liss Inc.",

number = "11",

}

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 - Funding Information: 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 Funding Information: 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. Funding Information: 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. Funding Information: 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. Publisher Copyright: © 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 - Genome-Wide Association Study (GWAS)

KW - SNP heritability

KW - brain expression pathway

KW - electroencephalography (EEG)

KW - endophenotype

KW - genetic correlation

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

C2 - 29947131

AN - SCOPUS:85054451120

SN - 1065-9471

VL - 39

SP - 4183

EP - 4195

JO - Human Brain Mapping

JF - Human Brain Mapping

IS - 11

ER -

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

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