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Published Online: 23 January 2015

Genetic Sources of Subcomponents of Event-Related Potential in the Dimension of Psychosis Analyzed From the B-SNIP Study

Balaji Narayanan, Ph.D., Lauren E. Ethridge, Ph.D., Kasey O’Neil, B.S., Sabra Dunn, B.S., Ian Mathew, B.S., Neeraj Tandon, B.S., Vince D. Calhoun, Ph.D., Gualberto Ruaño, M.D., Ph.D., Mohan Kocherla, M.S., Andreas Windemuth, Ph.D., Brett A. Clementz, Ph.D., Carol A. Tamminga, M.D., John A. Sweeney, Ph.D., Matcheri S. Keshavan, M.D., and Godfrey D. Pearlson, M.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 172, Number 5
https://doi.org/10.1176/appi.ajp.2014.13101411
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Abstract

Objective:

Biological risk factors underlying psychosis are poorly understood. Biological underpinnings of the dimension of psychosis can be derived using genetic associations with intermediate phenotypes such as subcomponents of auditory event-related potentials (ERPs). Various ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder are heritable and are expressed in unaffected relatives, although studies investigating genetic contributions to ERP abnormalities are limited. The authors used a novel parallel independent component analysis (para-ICA) to determine which empirically derived gene clusters are associated with data-driven ERP subcomponents, assuming a complex etiology underlying psychosis.

Method:

The authors examined the multivariate polygenic association of ERP subcomponents from 64-channel auditory oddball data in 144 individuals with schizophrenia, 210 psychotic bipolar disorder probands, and 95 healthy individuals from the multisite Bipolar-Schizophrenia Network on Intermediate Phenotypes study. Data were reduced by principal components analysis to two target and one standard ERP waveforms. Multivariate association of compressed ERP waveforms with a set of 20,329 single-nucleotide polymorphisms (SNPs) (reduced from a 1-million-SNP array) was examined using para-ICA. Genes associated with SNPs were further examined using pathway analysis tools.

Results:

Para-ICA identified four ERP components that were significantly correlated with three genetic components. Enrichment analysis revealed complement immune response pathway and multiple processes that significantly mediate ERP abnormalities in psychosis, including synaptic cell adhesion, axon guidance, and neurogenesis.

Conclusions:

This study identified three genetic components comprising multiple genes mediating ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder. The data suggest a possible polygenic structure comprising genes influencing key neurodevelopmental processes, neural circuitry, and brain function mediating biological pathways plausibly associated with psychosis.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 172 • Number 5 • May 01, 2015
Pages: 466 - 478
PubMed: 25615564

History

Received: 25 October 2013
Revision received: 30 April 2014
Revision received: 21 August 2014
Revision received: 10 September 2014
Accepted: 12 September 2014
Published online: 23 January 2015
Published in print: May 01, 2015

Authors

Affiliations

Balaji Narayanan, Ph.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Lauren E. Ethridge, Ph.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Kasey O’Neil, B.S.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Sabra Dunn, B.S.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Ian Mathew, B.S.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Neeraj Tandon, B.S.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Vince D. Calhoun, Ph.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Gualberto Ruaño, M.D., Ph.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Mohan Kocherla, M.S.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Andreas Windemuth, Ph.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Brett A. Clementz, Ph.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Carol A. Tamminga, M.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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John A. Sweeney, Ph.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Matcheri S. Keshavan, M.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Godfrey D. Pearlson, M.D.
From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Conn.; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; the Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque; the Mind Research Network, Albuquerque; the Genetics Research Center, Hartford Hospital, Hartford; Genomas, Inc., Hartford; the Department of Psychology, University of Georgia, Athens; and the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.
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Notes

Address correspondence to Dr. Narayanan ([email protected]).

Funding Information

National Institute of Mental Health10.13039/100000025: 2R44 MH075481, R01 MH077851, R01 MH077852, R01 MH077862, R01 MH077945, R01 MH078113
Supported by NIMH grants R01 MH077851 to Dr. Pearlson, MH078113 to Dr. Tamminga, MH077945 to Dr. Keshavan, MH077862 to Dr. Sweeney, and MH077852 to Dr. Gunavant Thaker. Additional support includes NIMH grants 2R44 MH075481 to Dr. Ruaño and NIH grants P20GM1034672 and R01EB006841 to Dr. Calhoun.

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