Hostname: page-component-cd9895bd7-gxg78 Total loading time: 0 Render date: 2024-12-27T06:55:28.715Z Has data issue: false hasContentIssue false
  • English
  • Français

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: cbousman@unimelb.edu.au)
Get access Rights & Permissions [Opens in a new window]

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 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

†

These authors contributed equally to this work.

References

Agarwal, A, Zhang, M, Trembak-Duff, I, Unterbarnscheidt, T, Radyushkin, K, Dibaj, P, Martins De Souza, D, Boretius, S, Brzozka, MM, Steffens, H, Berning, S, Teng, Z, Gummert, MN, Tantra, M, Guest, PC, Willig, KI, Frahm, J, Hell, SW, Bahn, S, Rossner, MJ, Nave, KA, Ehrenreich, H, Zhang, W, Schwab, MH (2014). Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity. Cell Reports 8, 1130–1145.CrossRefGoogle ScholarPubMed
Alba-Ferrara, LM, de Erausquin, GA (2013). What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia. Frontiers in Integrative Neuroscience 7, 9.CrossRefGoogle ScholarPubMed
Barrett, JC, Fry, B, Maller, J, Daly, MJ (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265.CrossRefGoogle ScholarPubMed
Bora, E, Fornito, A, Radua, J, Walterfang, M, Seal, M, Wood, SJ, Yucel, M, Velakoulis, D, Pantelis, C (2011). Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis. Schizophrenia Research 127, 46–57.CrossRefGoogle ScholarPubMed
Bousman, CA, Yung, AR, Pantelis, C, Ellis, JA, Chavez, RA, Nelson, B, Lin, A, Wood, SJ, Amminger, GP, Velakoulis, D, Mcgorry, PD, Everall, IP, Foley, DL (2013). Effects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis. Translational Psychiatry 3, E251.CrossRefGoogle ScholarPubMed
Castle, DJ, Jablensky, A, Mcgrath, JJ, Carr, V, Morgan, V, Waterreus, A, Valuri, G, Stain, H, Mcguffin, P, Farmer, A (2006). The diagnostic interview for psychoses (DIP): development, reliability and applications. Psychological Medicine 36, 69–80.CrossRefGoogle ScholarPubMed
Chen, YJ, Johnson, MA, Lieberman, MD, Goodchild, RE, Schobel, S, Lewandowski, N, Rosoklija, G, Liu, RC, Gingrich, JA, Small, S, Moore, H, Dwork, AJ, Talmage, DA, Role, LW (2008). Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 28, 6872–6883.CrossRefGoogle ScholarPubMed
Desikan, RS, Ségonne, F, Fischl, B, Quinn, BT, Dickerson, BC, Blacker, D, Buckner, RL, Dale, AM, Maguire, RP, Hyman, BT, Albert, MS, Killiany, RJ (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31, 968–980.CrossRefGoogle ScholarPubMed
Ellison-Wright, I, Bullmore, E (2009). Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophrenia Research 108, 3–10.CrossRefGoogle ScholarPubMed
Fischl, B, Salat, DH, Busa, E, Albert, M, Dieterich, M, Haselgrove, C, van der Kouwe, A, Killiany, R, Kennedy, D, Klaveness, S, Montillo, A, Makris, N, Rosen, B, Dale, AM (2002). Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33, 341–355.CrossRefGoogle ScholarPubMed
Fusar-Poli, P, Smieskova, R, Kempton, MJ, Ho, BC, Andreasen, NC, Borgwardt, S (2013). Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neuroscience and Biobehavioral Reviews 37, 1680–1691.CrossRefGoogle ScholarPubMed
Goh, S, Bansal, R, Xu, D, Hao, X, Liu, J, Peterson, BS (2011). Neuroanatomical correlates of intellectual ability across the life span. Developmental Cognitive Neuroscience 1, 305–312.CrossRefGoogle ScholarPubMed
Hall, J, Whalley, HC, Job, DE, Baig, BJ, Mcintosh, AM, Evans, KL, Thomson, PA, Porteous, DJ, Cunningham-Owens, DG, Johnstone, EC, Lawrie, SM (2006). A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nature Neuroscience 9, 1477–1478.CrossRefGoogle ScholarPubMed
Hedges, LV, Olkin, I (1985). Statistical Methods for Meta-Analysis. Academic Press: Orlando.Google Scholar
Keri, S, Kiss, I, Kelemen, O (2009). Effects of a neuregulin 1 variant on conversion to schizophrenia and schizophreniform disorder in people at high risk for psychosis. Molecular Psychiatry 14, 118–119.CrossRefGoogle ScholarPubMed
Kochunov, P, Glahn, DC, Lancaster, JL, Winkler, AM, Smith, S, Thompson, PM, Almasy, L, Duggirala, R, Fox, PT, Blangero, J (2010). Genetics of microstructure of cerebral white matter using diffusion tensor imaging. Neuroimage 53, 1109–1116.CrossRefGoogle ScholarPubMed
Law, AJ, Lipska, BK, Weickert, CS, Hyde, TM, Straub, RE, Hashimoto, R, Harrison, PJ, Kleinman, JE, Weinberger, DR (2006). Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proceedings of the National Academy of Sciences of the United States of America 103, 6747–6752.CrossRefGoogle ScholarPubMed
Loughland, C, Draganic, D, Mccabe, K, Richards, J, Nasir, A, Allen, J, Catts, S, Jablensky, A, Henskens, F, Michie, P, Mowry, B, Pantelis, C, Schall, U, Scott, R, Tooney, P, Carr, V (2011). Australian Schizophrenia Research Bank: a database of comprehensive clinical, endophenotypic and genetic data for aetiological studies of schizophrenia. Australian and New Zealand Journal of Psychiatry 44, 1029–1035.Google Scholar
Mata, I, Perez-Iglesias, R, Roiz-Santianez, R, Tordesillas-Gutierrez, D, Gonzalez-Mandly, A, Vazquez-Barquero, JL, Crespo-Facorro, B (2009). A neuregulin 1 variant is associated with increased lateral ventricle volume in patients with first-episode schizophrenia. Biological Psychiatry 65, 535–540.CrossRefGoogle ScholarPubMed
Mcintosh, AM, Moorhead, TW, Job, D, Lymer, GK, Munoz Maniega, S, Mckirdy, J, Sussmann, JE, Baig, BJ, Bastin, ME, Porteous, D, Evans, KL, Johnstone, EC, Lawrie, SM, Hall, J (2008). The effects of a neuregulin 1 variant on white matter density and integrity. Molecular Psychiatry 13, 1054–1059.CrossRefGoogle ScholarPubMed
Mostaid, MS, Lloyd, D, Liberg, B, Sundram, S, Pereira, A, Pantelis, C, Karl, T, Weickert, CS, Everall, IP, Bousman, CA (2016). Neuregulin-1 and schizophrenia in the genome-wide association study era. Neuroscience and Biobehavioral Reviews 68, 387–409.CrossRefGoogle ScholarPubMed
Mostaid, MS, Mancuso, SG, Liu, C, Sundram, S, Pantelis, C, Everall, IP, Bousman, CA (2017). Meta-analysis reveals associations between genetic variation in the 5′ and 3′ regions of neuregulin-1 and schizophrenia. Translational Psychiatry 7, E1004.CrossRefGoogle ScholarPubMed
Nickl-Jockschat, T, Stocker, T, Krug, A, Markov, V, Huang, R, Schneider, F, Habel, U, Eickhoff, SB, Zerres, K, Nothen, MM, Treutlein, J, Rietschel, M, Shah, NJ, Kircher, T (2014). A neuregulin-1 schizophrenia susceptibility variant causes perihippocampal fiber tract anomalies in healthy young subjects. Brain and Behavior 4, 215–226.CrossRefGoogle ScholarPubMed
Nicodemus, KK, Law, AJ, Luna, A, Vakkalanka, R, Straub, RE, Kleinman, JE, Weinberger, DR (2009). A 5′ promoter region SNP in NRG1 is associated with schizophrenia risk and type III isoform expression. Molecular Psychiatry 14, 741–743.CrossRefGoogle ScholarPubMed
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427.CrossRefGoogle Scholar
Song, SK, Sun, SW, Ju, WK, Lin, SJ, Cross, AH, Neufeld, AH (2003). Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20, 1714–1722.CrossRefGoogle ScholarPubMed
Song, SK, Yoshino, J, Le, TQ, Lin, SJ, Sun, SW, Cross, AH, Armstrong, RC (2005). Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage 26, 132–140.CrossRefGoogle ScholarPubMed
Suarez-Pinilla, P, Roiz-Santianez, R, Mata, I, Ortiz-Garcia De La Foz, V, Brambilla, P, Fananas, L, Valle-San Roman, N, Crespo-Facorro, B (2015). Progressive structural brain changes and NRG1 gene variants in first-episode nonaffective psychosis. Neuropsychobiology 71, 103–111.CrossRefGoogle ScholarPubMed
Taveggia, C, Thaker, P, Petrylak, A, Caporaso, GL, Toews, A, Falls, DL, Einheber, S, Salzer, JL (2008). Type III neuregulin-1 promotes oligodendrocyte myelination. Glia 56, 284–293.CrossRefGoogle ScholarPubMed
Weickert, CS, Tiwari, Y, Schofield, PR, Mowry, BJ, Fullerton, JM (2012). Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity. Translational Psychiatry 2, E104.CrossRefGoogle ScholarPubMed
Winterer, G, Konrad, A, Vucurevic, G, Musso, F, Stoeter, P, Dahmen, N (2008). Association of 5′ end neuregulin-1 (NRG1) gene variation with subcortical medial frontal microstructure in humans. Neuroimage 40, 712–718.CrossRefGoogle ScholarPubMed
Xu, J, Kober, H, Carroll, KM, Rounsaville, BJ, Pearlson, GD, Potenza, MN (2012). White matter integrity and behavioral activation in healthy subjects. Human Brain Mapping 33, 994–1002.CrossRefGoogle ScholarPubMed
Supplementary material: File

Bousman et al supplementary material

Bousman et al supplementary material 1

Download Bousman et al supplementary material(File)
File 200.9 KB