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Neuregulin-1 (NRG1) polymorphisms linked with psychosis transition are associated with enlarged lateral ventricles and white matter disruption in schizophrenia

Published online by Cambridge University Press:  22 August 2017

C. A. Bousman ,
V. Cropley ,
P. Klauser ,
J. L. Hess ,
A. Pereira ,
R. Idrizi ,
J. Bruggemann ,
M. S. Mostaid ,
R. Lenroot  and
T. W. Weickert
...Show all authors
C. A. Bousman*
Affiliation:
Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia Department of General Practice, The University of Melbourne, Parkville, VIC, Australia Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorne, VIC, Australia Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
V. Cropley
Affiliation:
Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia
P. Klauser
Affiliation:
Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, VIC, Australia
J. L. Hess
Affiliation:
Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York
A. Pereira
Affiliation:
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
R. Idrizi
Affiliation:
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
J. Bruggemann
Affiliation:
Schizophrenia Research Institute, Sydney, Australia Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, Australia
M. S. Mostaid
Affiliation:
Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia
R. Lenroot
Affiliation:
Schizophrenia Research Institute, Sydney, Australia Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, Australia
T. W. Weickert
Affiliation:
Schizophrenia Research Institute, Sydney, Australia Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, Australia
S. J. Glatt
Affiliation:
Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York
I. P. Everall
Affiliation:
Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia NorthWestern Mental Health, Melbourne, Victoria, Australia
S. Sundram
Affiliation:
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia NorthWestern Mental Health, Melbourne, Victoria, Australia Department of Psychiatry, School of Clinical Sciences, Monash University and Monash Health, Clayton, Victoria, Australia
A. Zalesky
Affiliation:
Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia Department of Biomedical Engineering, University of Melbourne, Parkville, VIC, Australia
C. S. Weickert
Affiliation:
Schizophrenia Research Institute, Sydney, Australia Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, Australia
C. Pantelis
Affiliation:
Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia Schizophrenia Research Institute, Sydney, Australia NorthWestern Mental Health, Melbourne, Victoria, Australia
*
*Address for correspondence: Dr C. A. Bousman, Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne, 161 Barry Street, Level 3, Parkville, VIC, Australia. (Email: [email protected])
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Abstract

Background

Two single-nucleotide polymorphisms (SNPs) (rs4281084 and rs12155594) within the neuregulin-1 (NRG1) gene have been associated with psychosis transition. However, the neurobiological changes associated with these SNPs remain unclear. We aimed to determine what relationship these two SNPs have on lateral ventricular volume and white matter integrity, as abnormalities in these brain structures are some of the most consistent in schizophrenia.

Methods

Structural (n = 370) and diffusion (n = 465) magnetic resonance imaging data were obtained from affected and unaffected individuals predominantly of European descent. The SNPs rs4281084, rs12155594, and their combined allelic load were examined for their effects on lateral ventricular volume, fractional anisotropy (FA) as well as axial (AD) and radial (RD) diffusivity. Additional exploratory analyses assessed NRG1 effects on gray matter volume, cortical thickness, and surface area throughout the brain.

Results

Individuals with a schizophrenia age of onset ⩽25 and a combined allelic load ⩾3 NRG1 risk alleles had significantly larger right (up to 50%, p adj = 0.01) and left (up to 45%, p adj = 0.05) lateral ventricle volumes compared with those with allelic loads of less than three. Furthermore, carriers of three or more risk alleles, regardless of age of onset and case status, had significantly reduced FA and elevated RD but stable AD in the frontal cortex compared with those carrying fewer than three risk alleles.

Conclusions

Our findings build on a growing body of research supporting the functional importance of genetic variation within the NRG1 gene and complement previous findings implicating the rs4281084 and rs12155594 SNPs as markers for psychosis transition.

Keywords

Fractional anisotropylateral ventriclesneuregulin-1neuroimagingpolymorphism
Type
Original Articles
Information
Psychological Medicine , Volume 48 , Issue 5 , April 2018 , pp. 801 - 809
Copyright
Copyright © Cambridge University Press 2017 

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Footnotes

†

These authors contributed equally to this work.

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