Disruption of the neurexin 1 gene is associated with schizophrenia
Open accessAbstract
Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.
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The neurexin-1 (nrxn1) gene has been linked directly to ASD and SCZ.
“Of these, the neurexin-1 (nrxn1) gene has been linked directly to ASD and SCZ (Kim et al. 2008; Rujescu et al. 2009, Glessner et al. 2009; Ching et al. 2010; Gauthier et al. 2011).”
From Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia (2025) · cites this paper as Rujescu et al. 2009
Our estimate of the de novo rate is comparable with more recent estimates in autism.
“but is comparable with more recent estimates in autism.25, 29, 30”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [29]
Among genes previously reported to have potential connections between rare variants and schizophrenia, the authors identified an ultra-rare splice donor variant in TAF13, an ultra-rare nonsense variant in SETD1A, and a single ultra-rare nonsense variant in NRXN1.
“we identified an ultra-rare splice donor variant in TAF1312, an ultra-rare nonsense variant in SETD1A16,17, and a single ultra-rare nonsense variant in NRXN1, a gene in which exonic deletions associate with schizophrenia18.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [18]
Even the largest genome-wide scans, typically under 10,000 samples, remain underpowered to robustly confirm genetic association for most pathogenic CNVs reported so far, particularly those with low frequencies or intermediate effect sizes.
“yet even the largest genome-wide scans (sample sizes typically <10,000) remain under-powered to robustly confirm genetic association for the majority of pathogenic CNVs reported so far, particularly for those with low frequencies (<0.5% in cases) or intermediate effect sizes (odds ratios 2–10).”
From Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects (2017) · cites this paper as [9]
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- Authors
- Rujescu, D., Ingason, A., Cichon, S., Pietiläinen, O. P. H., Barnes, M. R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A., Olason, P. I., Hardarsson, G., Jonsdottir, G. A., Gustafsson, O., Fossdal, R., Giegling, I., Möller, H.-J., Hartmann, A. M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O. A., Hansen, T., Werge, T., Kiemeney, L. A., Franke, B., Veltman, J., Buizer-Voskamp, J. E., GROUP Investigators, Sabatti, C., Ophoff, R. A., Rietschel, M., Nöthen, M. M., Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., & Collier, D. A.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- deCODE genetics, Reykjavík, Iceland
- University of Bonn (DE)
- Department for Molecular Medicine, National Public Health Institute, Helsinki, Finland
- GlaxoSmithKline (United Kingdom) (GB)
- King's College London (GB)
- University of Verona (IT)
- deCODE Genetics (Iceland) (IS)
- Department of Psychiatry, National University Hospital, Reykjavík, Iceland
- National University Hospital of Iceland (IS)
- Department of Genomics, Life and Brain Center
- University of Aberdeen (GB)
- Ravenscraig Hospital, Greenock, Scotland
- Department of Mental Health and Addiction, National Public Health Institute, Helsinki, Finland
- Oslo University Hospital (NO)
- Sankt Hans Hospital (DK)
- Department of Epidemiology and Biostatistics (133 EPIB)
- Radboud University Nijmegen (NL)
- Rudolf Magnus Institute of Neuroscience, Department of Psychiatry
- University of California, Los Angeles (US)
- Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig- Maximilians University, Munich, Germany
- Broad Institute (US)
- Department of Mental Health, University of Aberdeen, Aberdeen, Scotland
- Corresponding author
- Collier, David A.
- ORCID
- Rujescu, Dan
- Cichon, Sven
- Pietiläinen, Olli P.H.
- Barnes, Michael R.
- Toulopoulou, Timothea
- Picchioni, Marco
- Vassos, Evangelos
- Ettinger, Ulrich
- Bramon, Elvira
- Murray, Robin
- Ruggeri, Mirella
- Tosato, Sarah
- Bonetto, Chiara
- Steinberg, Stacy
- Gylfason, Arnaldur
- Olason, Pall I.
- Giegling, Ina
- Möller, Hans-Jürgen
- Hartmann, Annette M.
- Hoffmann, Per
- Suvisaari, Jaana
- Djurovic, Srdjan
- Melle, Ingrid
- Andreassen, Ole A.
- Hansen, Thomas
- Werge, Thomas
- Kiemeney, Lambertus A.
- Franke, Barbara
- Veltman, Joris
- Sabatti, Chiara
- Ophoff, Roel A.
- Rietschel, Marcella
- Nöthen, Markus M.
- Peltonen, Leena
- Collier, David A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-10-22
- Volume
- 18
- Issue
- 5
- Pages
- 988-996
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2695245
- OpenAlex
- W2106949460
- Cited by
- 471
- References
- 44
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 19 · 2023: 6 · 2022: 8 · 2021: 11 · 2020: 12 · 2019: 21 · 2018: 19 · 2017: 22 · 2016: 21 · 2015: 22 · 2014: 31 · 2013: 39 · 2012: 52
- FWCI
- 33.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- VU Research Portal (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- Wellcome Trust (089061)
- National Institute for Health and Care Research (PDA/02/06/016)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- schizophrenia, NRXN1, copy number variation, gene deletion, de novo deletion, genetic risk, NRXN3
- MeSH terms
- Adolescent, Adult, Calcium-Binding Proteins, Exons, Female, Humans, Male, Nerve Tissue Proteins, Schizophrenia, Cell Adhesion Molecules, Neuronal, Case-Control Studies, Gene Deletion, Gene Dosage, Neural Cell Adhesion Molecules, Genetic Predisposition to Disease, Gene Duplication, Gene Silencing, White People, Young Adult
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