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Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci

Published online by Cambridge University Press:  20 December 2016

M. Liu ,
S. M. Malone ,
U. Vaidyanathan ,
M. C. Keller ,
G. Abecasis ,
M. McGue ,
W. G. Iacono  and
S. I. Vrieze
M. Liu
Affiliation:
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA
S. M. Malone
Affiliation:
Department of Psychology, University of Minnesota, Minneapolis, MN, USA
U. Vaidyanathan
Affiliation:
National Institutes of Health, Bethesda, MD, USA
M. C. Keller
Affiliation:
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA
G. Abecasis
Affiliation:
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
M. McGue
Affiliation:
Department of Psychology, University of Minnesota, Minneapolis, MN, USA
W. G. Iacono
Affiliation:
Department of Psychology, University of Minnesota, Minneapolis, MN, USA
S. I. Vrieze*
Affiliation:
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA
*
*Address for correspondence: S. I. Vrieze, Ph.D., Institute for Behavioral Genetics, University of Colorado Boulder, 1480 30th Street, Boulder, CO 80303, USA. (Email: scott.vrieze@colorado.edu)
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Abstract

Background

Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes.

Method

We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential.

Results

Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing.

Conclusions

The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk.

Keywords

Endophenotypesgene-based testspolygenic risk scoresschizophreniasingle variant association
Type
Original Articles
Information
Psychological Medicine , Volume 47 , Issue 6 , April 2017 , pp. 1116 - 1125
Creative Commons
This is a work of the U.S. Government and is not subject to copyright protection in the United States.
Copyright
Copyright © Cambridge University Press 2016

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