Loss-of-Function Variants in Schizophrenia Risk and SETD1A as a Candidate Susceptibility Gene
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Loss-of-function (LOF) (i.e., nonsense, splice site, and frameshift) variants that lead to disruption of gene function are likely to contribute to the etiology of neuropsychiatric disorders. Here, we perform a systematic investigation of the role of both de novo and inherited LOF variants in schizophrenia using exome sequencing data from 231 case and 34 control trios. We identify two de novo LOF variants in the SETD1A gene, which encodes a subunit of histone methyltransferase, a finding unlikely to have occurred by chance, and provide evidence for a more general role of chromatin regulators in schizophrenia risk. Transmission pattern analyses reveal that LOF variants are more likely to be transmitted to affected individuals than controls. This is especially true for private LOF variants in genes intolerant to functional genetic variation. These findings highlight the contribution of LOF mutations to the genetic architecture of schizophrenia and provide important insights into disease pathogenesis.
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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 [16]
The current analysis did not implicate individual genes of large effect in an unbiased exome-wide search while documenting a clear exome-wide elevation of hundreds of pathogenic variants across 4,877 schizophrenia cases relative to controls, lending support to high polygenicity of schizophrenia extending to rare as well as common variants.
“The fact that an analysis of the current scale (4,877 cases, 6,203 controls, and 45,376 other genomes used to help identify ultra-rare variants) did not implicate individual genes of large effect in an unbiased exome-wide search – while documenting a very clear exome-wide elevation of hundreds of pathogenic variants across 4,877 individuals affected with schizophrenia relative to controls – lends”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [16]
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References 63 · Cited by 204
- Authors
- Takata, A., Xu, B., Ionita-Laza, I., Roos, J. L., Gogos, J. A., & Karayiorgou, M.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Gogos, Joseph A.
- Karayiorgou, Maria
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 82
- Issue
- 4
- Pages
- 773-780
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4387883
- OpenAlex
- W2086039500
- Cited by
- 204
- References
- 63
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 13 · 2023: 15 · 2022: 18 · 2021: 11 · 2020: 21 · 2019: 35 · 2018: 16 · 2017: 15 · 2016: 21 · 2015: 11 · 2014: 6
- FWCI
- 13.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UpSpace Institutional Repository (University of Pretoria) (submittedVersion)
- Funders
- National Institute of Mental Health (MH061399, R01MH061399, R01MH097879, MH097879, R01MH095797)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- schizophrenia, loss-of-function mutations, SETD1A, de novo mutations, inherited mutations, histone methyltransferase, chromatin regulators, genetic susceptibility
- MeSH terms
- Female, Gene Frequency, Genotype, Humans, Male, Histone-Lysine N-Methyltransferase, Risk Factors, Schizophrenia, Genetic Variation, Cohort Studies, Genome, Human, Likelihood Functions, Sequence Analysis, DNA, Genetic Predisposition to Disease, Chromatin Assembly and Disassembly, Gene Regulatory Networks
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