Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands

Bruce I. Turetsky; Tiffany A. Greenwood; Ann Olincy; Allen D. Radant; David L. Braff; Kristin S. Cadenhead; Dorcas J. Dobie; Robert Freedman; Michael F. Green; Raquel E. Gur; Ruben C. Gur; Gregory A. Light; James Mintz; Keith H. Nuechterlein; Nicholas J. Schork; Larry J. Seidman; Larry J. Siever; Jeremy M. Silverman; William S. Stone; Neal R. Swerdlow; Debby W. Tsuang; Ming T. Tsuang; Monica E. Calkins

doi:10.1016/j.biopsych.2008.06.018

Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands

Bruce I. Turetsky
, Tiffany A. Greenwood
, Ann Olincy
, Allen D. Radant
, David L. Braff
, Kristin S. Cadenhead
, Dorcas J. Dobie
, Robert Freedman
, Michael F. Green
, Raquel E. Gur
, Ruben C. Gur
, Gregory A. Light
, James Mintz
, Keith H. Nuechterlein
, Nicholas J. Schork
, Larry J. Seidman
, Larry J. Siever
, Jeremy M. Silverman
, William S. Stone
, Neal R. Swerdlow

Debby W. Tsuang, Ming T. Tsuang, Monica E. Calkins

University of Pennsylvania
University of California at San Diego
University of Colorado Anschutz Medical Campus
University of Washington
University of California at Los Angeles
Department of Veterans Affairs
Scripps Research Institute
Harvard University
Icahn School of Medicine at Mount Sinai
VA Medical Center
Clinical Center

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

106 Scopus citations

Abstract

Background: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes. Methods: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity. Results: Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio. Conclusions: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.

Original language	English
Pages (from-to)	1051-1059
Number of pages	9
Journal	Biological Psychiatry
Volume	64
Issue number	12
DOIs	https://doi.org/10.1016/j.biopsych.2008.06.018
State	Published - 15 Dec 2008
Externally published	Yes

Bibliographical note

Funding Information:
This research was conducted by the Consortium on the Genetics of Schizophrenia (COGS) and supported by collaborative RO1 Grants from the National Institute of Mental Health to the following institutions: Harvard University RO1- MH065562 ; Mount Sinai School of Medicine RO1- MH065554 ; University of California Los Angeles RO1-MH65707; University of California San Diego R01- MH065571 ; University of Colorado RO1-MH65588; University of Pennsylvania RO1-MH65578; and University of Washington R01-MH65558. Additional grant support for this study was provided by MH064045 (BIT), MH43292 (MFG), and MH79777 (GAL).

Funding Information:
Dr. Turetsky has received research grant support from Astra-Zeneca Pharmaceuticals, Inc. Dr. Braff has received consulting fees from Medical Summit series, Acadia, Johnson and Johnson Genomics, and Hoffman-La Roche Inc. Equities are held in mutual funds or closed funds controlled by others. Dr. Freedman has a patent on the CHRNα7 sequence through the Department of Veterans Affairs. Dr. Green has been a consultant for Amgen, Acadia, Astellas, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eli Lilly, Lundbeck, Memory Pharmaceuticals, Otsuka Pharmaceutical, Sanofi-Aventis Pharmaceuticals, and Solvay Pharmaceuticals. Dr. Neuchterlein has received research grant support from Janssen Pharmaceuticals. Dr. Seidman has received an unrestricted grant for educational purposes Janssen Pharmaceuticals. Dr. Swerdlow has received consulting honoraria from Allergan, Inc. and research support from Pfizer Pharmaceuticals and Allergan, Inc. All other authors report no biomedical financial interests or potential conflicts of interest relevant to the subject matter of this article.

Funding

This research was conducted by the Consortium on the Genetics of Schizophrenia (COGS) and supported by collaborative RO1 Grants from the National Institute of Mental Health to the following institutions: Harvard University RO1- MH065562 ; Mount Sinai School of Medicine RO1- MH065554 ; University of California Los Angeles RO1-MH65707; University of California San Diego R01- MH065571 ; University of Colorado RO1-MH65588; University of Pennsylvania RO1-MH65578; and University of Washington R01-MH65558. Additional grant support for this study was provided by MH064045 (BIT), MH43292 (MFG), and MH79777 (GAL). Dr. Turetsky has received research grant support from Astra-Zeneca Pharmaceuticals, Inc. Dr. Braff has received consulting fees from Medical Summit series, Acadia, Johnson and Johnson Genomics, and Hoffman-La Roche Inc. Equities are held in mutual funds or closed funds controlled by others. Dr. Freedman has a patent on the CHRNα7 sequence through the Department of Veterans Affairs. Dr. Green has been a consultant for Amgen, Acadia, Astellas, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eli Lilly, Lundbeck, Memory Pharmaceuticals, Otsuka Pharmaceutical, Sanofi-Aventis Pharmaceuticals, and Solvay Pharmaceuticals. Dr. Neuchterlein has received research grant support from Janssen Pharmaceuticals. Dr. Seidman has received an unrestricted grant for educational purposes Janssen Pharmaceuticals. Dr. Swerdlow has received consulting honoraria from Allergan, Inc. and research support from Pfizer Pharmaceuticals and Allergan, Inc. All other authors report no biomedical financial interests or potential conflicts of interest relevant to the subject matter of this article.

Funders	Funder number
Allergan, Inc.
Astra-Zeneca Pharmaceuticals, Inc.
National Institute of Mental Health	R01MH065554
California Sea Grant, University of California, San Diego	MH065571
Asian American Studies Center, University of California Los Angeles	RO1-MH65707
University of Pennsylvania	RO1-MH65578
Harvard University	RO1- MH065562
Icahn School of Medicine at Mount Sinai	RO1- MH065554
University of Washington	MH43292, MH79777, R01-MH65558, MH064045
Janssen Pharmaceuticals
University of Colorado	RO1-MH65588
Pfizer Pharmaceuticals

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Endophenotype
N100
evoked potential
gating
heritability
schizophrenia

Access to Document

10.1016/j.biopsych.2008.06.018

Cite this

Turetsky, B. I., Greenwood, T. A., Olincy, A., Radant, A. D., Braff, D. L., Cadenhead, K. S., Dobie, D. J., Freedman, R., Green, M. F., Gur, R. E., Gur, R. C., Light, G. A., Mintz, J., Nuechterlein, K. H., Schork, N. J., Seidman, L. J., Siever, L. J., Silverman, J. M., Stone, W. S., ... Calkins, M. E. (2008). Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands. Biological Psychiatry, 64(12), 1051-1059. https://doi.org/10.1016/j.biopsych.2008.06.018

@article{d757d7225041475e9952fa421476f8b9,

title = "Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands",

abstract = "Background: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes. Methods: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either {"}broad{"} or {"}narrow,{"} based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity. Results: Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio. Conclusions: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.",

keywords = "Endophenotype, N100, evoked potential, gating, heritability, schizophrenia",

author = "Turetsky, \{Bruce I.\} and Greenwood, \{Tiffany A.\} and Ann Olincy and Radant, \{Allen D.\} and Braff, \{David L.\} and Cadenhead, \{Kristin S.\} and Dobie, \{Dorcas J.\} and Robert Freedman and Green, \{Michael F.\} and Gur, \{Raquel E.\} and Gur, \{Ruben C.\} and Light, \{Gregory A.\} and James Mintz and Nuechterlein, \{Keith H.\} and Schork, \{Nicholas J.\} and Seidman, \{Larry J.\} and Siever, \{Larry J.\} and Silverman, \{Jeremy M.\} and Stone, \{William S.\} and Swerdlow, \{Neal R.\} and Tsuang, \{Debby W.\} and Tsuang, \{Ming T.\} and Calkins, \{Monica E.\}",

note = "Funding Information: This research was conducted by the Consortium on the Genetics of Schizophrenia (COGS) and supported by collaborative RO1 Grants from the National Institute of Mental Health to the following institutions: Harvard University RO1- MH065562 ; Mount Sinai School of Medicine RO1- MH065554 ; University of California Los Angeles RO1-MH65707; University of California San Diego R01- MH065571 ; University of Colorado RO1-MH65588; University of Pennsylvania RO1-MH65578; and University of Washington R01-MH65558. Additional grant support for this study was provided by MH064045 (BIT), MH43292 (MFG), and MH79777 (GAL). Funding Information: Dr. Turetsky has received research grant support from Astra-Zeneca Pharmaceuticals, Inc. Dr. Braff has received consulting fees from Medical Summit series, Acadia, Johnson and Johnson Genomics, and Hoffman-La Roche Inc. Equities are held in mutual funds or closed funds controlled by others. Dr. Freedman has a patent on the CHRNα7 sequence through the Department of Veterans Affairs. Dr. Green has been a consultant for Amgen, Acadia, Astellas, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eli Lilly, Lundbeck, Memory Pharmaceuticals, Otsuka Pharmaceutical, Sanofi-Aventis Pharmaceuticals, and Solvay Pharmaceuticals. Dr. Neuchterlein has received research grant support from Janssen Pharmaceuticals. Dr. Seidman has received an unrestricted grant for educational purposes Janssen Pharmaceuticals. Dr. Swerdlow has received consulting honoraria from Allergan, Inc. and research support from Pfizer Pharmaceuticals and Allergan, Inc. All other authors report no biomedical financial interests or potential conflicts of interest relevant to the subject matter of this article.",

year = "2008",

month = dec,

day = "15",

doi = "10.1016/j.biopsych.2008.06.018",

language = "אנגלית",

volume = "64",

pages = "1051--1059",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

number = "12",

}

Turetsky, BI, Greenwood, TA, Olincy, A, Radant, AD, Braff, DL, Cadenhead, KS, Dobie, DJ, Freedman, R, Green, MF, Gur, RE, Gur, RC, Light, GA, Mintz, J, Nuechterlein, KH, Schork, NJ, Seidman, LJ, Siever, LJ, Silverman, JM, Stone, WS, Swerdlow, NR, Tsuang, DW, Tsuang, MT & Calkins, ME 2008, 'Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands', Biological Psychiatry, vol. 64, no. 12, pp. 1051-1059. https://doi.org/10.1016/j.biopsych.2008.06.018

TY - JOUR

T1 - Abnormal Auditory N100 Amplitude

T2 - A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands

AU - Turetsky, Bruce I.

AU - Greenwood, Tiffany A.

AU - Olincy, Ann

AU - Radant, Allen D.

AU - Braff, David L.

AU - Cadenhead, Kristin S.

AU - Dobie, Dorcas J.

AU - Freedman, Robert

AU - Green, Michael F.

AU - Gur, Raquel E.

AU - Gur, Ruben C.

AU - Light, Gregory A.

AU - Mintz, James

AU - Nuechterlein, Keith H.

AU - Schork, Nicholas J.

AU - Seidman, Larry J.

AU - Siever, Larry J.

AU - Silverman, Jeremy M.

AU - Stone, William S.

AU - Swerdlow, Neal R.

AU - Tsuang, Debby W.

AU - Tsuang, Ming T.

AU - Calkins, Monica E.

N1 - Funding Information: This research was conducted by the Consortium on the Genetics of Schizophrenia (COGS) and supported by collaborative RO1 Grants from the National Institute of Mental Health to the following institutions: Harvard University RO1- MH065562 ; Mount Sinai School of Medicine RO1- MH065554 ; University of California Los Angeles RO1-MH65707; University of California San Diego R01- MH065571 ; University of Colorado RO1-MH65588; University of Pennsylvania RO1-MH65578; and University of Washington R01-MH65558. Additional grant support for this study was provided by MH064045 (BIT), MH43292 (MFG), and MH79777 (GAL). Funding Information: Dr. Turetsky has received research grant support from Astra-Zeneca Pharmaceuticals, Inc. Dr. Braff has received consulting fees from Medical Summit series, Acadia, Johnson and Johnson Genomics, and Hoffman-La Roche Inc. Equities are held in mutual funds or closed funds controlled by others. Dr. Freedman has a patent on the CHRNα7 sequence through the Department of Veterans Affairs. Dr. Green has been a consultant for Amgen, Acadia, Astellas, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eli Lilly, Lundbeck, Memory Pharmaceuticals, Otsuka Pharmaceutical, Sanofi-Aventis Pharmaceuticals, and Solvay Pharmaceuticals. Dr. Neuchterlein has received research grant support from Janssen Pharmaceuticals. Dr. Seidman has received an unrestricted grant for educational purposes Janssen Pharmaceuticals. Dr. Swerdlow has received consulting honoraria from Allergan, Inc. and research support from Pfizer Pharmaceuticals and Allergan, Inc. All other authors report no biomedical financial interests or potential conflicts of interest relevant to the subject matter of this article.

PY - 2008/12/15

Y1 - 2008/12/15

N2 - Background: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes. Methods: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity. Results: Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio. Conclusions: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.

AB - Background: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes. Methods: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity. Results: Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio. Conclusions: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.

KW - Endophenotype

KW - N100

KW - evoked potential

KW - gating

KW - heritability

KW - schizophrenia

UR - https://www.scopus.com/pages/publications/56349140522

U2 - 10.1016/j.biopsych.2008.06.018

DO - 10.1016/j.biopsych.2008.06.018

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C2 - 18701089

AN - SCOPUS:56349140522

SN - 0006-3223

VL - 64

SP - 1051

EP - 1059

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 12

ER -

Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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