Abstract
Linkage of 10q22-q23 to schizophrenia and the recently reported association of Neuregulin 3 (NRG3) polymorphisms with high ‘delusion factor’ scores led us to attempt replication and further refinement of these findings in a sample of 411 schizophrenic patients and 223 nonpsychiatric control subjects. Using quantitative cognitive traits, patients were grouped into a cluster with pervasive cognitive deficit (CD) and a cluster with relatively spared cognition (CS). We found a significant association between rs6584400 and schizophrenia, with a trend for rs10883866. Post hoc analysis revealed that this result was mainly due to the CS cluster, characterized by elevated scores on Schneiderian first-rank symptoms, salience of complex delusions and positive thought disorder—thus closely related to the ‘delusion factor’. In addition, both rs6584400 and rs10883866 were associated with the degraded-stimulus continuous performance task in which ‘risk’ alleles were associated with better than average performance in patients and worse performance in controls. This suggests that NRG3 may be modulating early attentional processes for perceptual sensitivity and vigilance, with opposite effects in affected individuals and healthy controls. The two single-nucleotide polymorphisms are in close proximity to the alternative first exons of the NRG3-a, -b and -d isoforms, of which the human brain-specific NRG-b appears to be the most interesting candidate.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chen PL, Avramopoulos D, Lasseter VK, McGrath JA, Fallin MD, Liang KY et al. Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. Am J Hum Genet 2009; 84: 21–34.
McGrath JA, Avramopoulos D, Lasseter VK, Wolyniec PS, Fallin MD, Liang KY et al. Familiality of novel factorial dimensions of schizophrenia. Arch Gen Psychiatry 2009; 66: 591–600.
Falls DL . Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003; 284: 14–30.
Carpenter G . ErbB-4: mechanism of action and biology. Exp Cell Res 2003; 284: 66–77.
Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.
Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci USA 2006; 103: 6747–6752.
Tan W, Wang Y, Gold B, Chen J, Dean M, Harrison PJ et al. Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. J Biol Chem 2007; 282: 24343–24351.
Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D et al. Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 2003; 73: 601–611.
Faraone SV, Hwu HG, Liu CM, Chen WJ, Tsuang MM, Liu SK et al. Genome scan of Han Chinese schizophrenia families from Taiwan: confirmation of linkage to 10q22.3. Am J Psychiatry 2006; 163: 1760–1766.
Balciuniene J, Feng N, Iyadurai K, Hirsch B, Charnas L, Bill BR et al. Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities. Am J Hum Genet 2007; 80: 938–947.
Benzel I, Bansal A, Browning BL, Galwey NW, Maycox PR, McGinnis R et al. Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia. Behav Brain Funct 2007; 3: 31.
Wang YC, Chen JY, Chen ML, Chen CH, Lai IC, Chen TT et al. Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. Biol Psychiatry 2008; 64: 1093–1096.
Xu B, Woodroffe A, Rodriguez-Murillo L, Roos JL, van Rensburg EJ, Abecasis GR et al. Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans. Proc Natl Acad Sci USA 2009; 106: 16746–16751.
Hallmayer JF, Kalaydjieva L, Badcock J, Dragovic M, Howell S, Michie PT et al. Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. Am J Hum Genet 2005; 77: 468–476.
Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Jablensky A et al. SCAN: Schedules For Clinical Assessment In Neuropsychiatry. Arch Gen Psychiatry 1990; 47: 589–593.
Castle DJ, Jablensky A, McGrath JJ, Carr V, Morgan V, Waterreus A et al. The diagnostic interview for psychoses (DIP): development, reliability and applications. Psychol Med 2005; 36: 69–80.
Manton KG, Woodbury MA, Tolley DH . Statistical Applications Using Fuzzy Sets. John Wiley: NewYork, 1994.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Jablensky A . Subtyping schizophrenia: implications for genetic research. Mol Psychiatry 2006; 11: 815–836.
Waters FA, Badcock JC, Dragovic M, Jablensky A . Neuropsychological functioning in schizophrenia patients with first-rank (passivity) symptoms. Psychopathology 2009; 42: 47–58.
Schneider K . Clinical Psychopathology (trans. MW Hamilton) Grune and Stratton: New York, 1959.
Nuechterlein KH . Signal detection in vigilance tasks and behavioral attributes among offspring of schizophrenic mothers and among hyperactive children. J Abnorm Psychol 1983; 92: 4–28.
Siegel BV, Nuechterlein KH, Abel L, Wu JC, Buchsbaum MS . Glucose metabolic correlates of continuous performance test performance in adults with a history of infantile autism, schizophrenics and controls. Schizophr Res 1995; 17: 85–94.
Gur RE, Calkins ME, Gur RC, Horan WP, Nuechterlein KH, Seidman LJ et al. The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes. Schizophr Bull 2007; 33: 49–68.
Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. PNAS 2003; 100: 6186–6191.
Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AFT . Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 2007; 10: 376–384.
Christie-Fougere MM, Darby-King A, Harley CW, McLean JH . Calcineurin inhibition eliminates the normal inverted U curve, enhances acquisition and prolongs memory in a mammalian 3′-5′-cyclic AMP-dependent learning paradigm. Neuroscience 2009; 158: 1277–1283.
Longart M, Liu Y, Karavanova I, Buonanno A . Neuregulin-2 is developmentally regulated and targeted to dendrites of central neurons. J Comp Neurol 2004; 472: 156–172.
Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y et al. Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci USA 1997; 94: 9562–9567.
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 2004; 101: 6062–6067.
Carteron C, Ferrer-Montiel A, Cabedo H . Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival. J Cell Sci 2006; 119: 898–909.
Acknowledgements
We thank the patients, family members and other volunteers who participated in the study and the staff of the North Metropolitan Health Area mental health services in Western Australia for assistance in patient recruitment. The study was supported by Grant #37580400 and #37580900 of the National Health and Medical Research Council of Australia to Professor A Jablensky and Professor L Kalaydjieva, with funding contribution from the North Metropolitan Health Area, Perth, Western Australia.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
URLs used in this study:
http://www.cbil.upenn.edu/cgi-bin/tess/tess
http://asp.ii.uib.no:8090/cgi-bin/CONSITE/consite
http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/
http://blast.ncbi.nlm.nih.gov/Blast.cgi
http://biogps.gnf.org/#goto=welcome
http://www.spss.com/worldwide/
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Supplementary information
PowerPoint slides
Rights and permissions
About this article
Cite this article
Morar, B., Dragović, M., Waters, F. et al. Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. Mol Psychiatry 16, 860–866 (2011). https://doi.org/10.1038/mp.2010.70
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2010.70
Keywords
This article is cited by
-
Selection signatures of Fuzhong Buffalo based on whole-genome sequences
BMC Genomics (2020)
-
Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype
Molecular Psychiatry (2020)
-
Neuregulin 3 rs10748842 polymorphism contributes to the effect of body mass index on cognitive impairment in patients with schizophrenia
Translational Psychiatry (2020)
-
A Systematic Review of Studies Reporting Data-Driven Cognitive Subtypes across the Psychosis Spectrum
Neuropsychology Review (2020)
-
Gene expression patterns of chicken neuregulin 3 in association with copy number variation and frameshift deletion
BMC Genetics (2017)