The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability
Open accessAbstract
By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.
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A large share of between-person variation in schizophrenia risk is genetic and involves many common alleles, rare copy number variants, and rare coding variants.
“Much of the between-individual variation in risk is genetic, involving large numbers of common alleles,5 rare copy number variants (CNVs)6, and rare coding variants (RCVs)7,8.”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [7]
Earlier sequencing studies established that ultra-rare and de novo mutations contribute to schizophrenia risk and found enrichment in neuronal genes and synaptic processes.
“Earlier schizophrenia sequencing studies have established that ultra-rare and de novo mutations contribute to risk as a category, and have prioritized disease-relevant tissues and processes, specifically observing an enrichment in neuronal genes and synaptic processes9,11,19–23.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [11]
Schizophrenia risk alleles are concentrated in genes nearly depleted of PTVs in population studies, as in other neurodevelopmental disorders, suggesting strong selection against such mutations.
“Furthermore, these risk alleles are concentrated in genes with a near-complete depletion of protein-truncating variants in population studies, a result shared with other neurodevelopmental disorders9,11 and suggesting strong direct selection against such mutations.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [11]
Schizophrenia has a substantial genetic component with contributions across the allele frequency spectrum.
“It is well-established that schizophrenia has a substantial genetic component with contributions from across the allele frequency spectrum8–11.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [11]
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- Authors
- Singh, T., Walters, J. T. R., Johnstone, M., Curtis, D., Suvisaari, J., Torniainen, M., Rees, E., Iyegbe, C., Blackwood, D., McIntosh, A. M., Kirov, G., Geschwind, D., Murray, R. M., Di Forti, M., Bramon, E., Gandal, M., Hultman, C. M., Sklar, P., Study, I., UK10K Consortium, Palotie, A., Sullivan, P. F., O'Donovan, M. C., Owen, M. J., & Barrett, J. C.
- Affiliations
- Wellcome Sanger Institute (GB)
- Cardiff University (GB)
- Royal Edinburgh Hospital (GB)
- Queen Mary University of London (GB)
- Finnish Institute for Health and Welfare (FI)
- King's College London (GB)
- University of Edinburgh (GB)
- University of California, Los Angeles (US)
- University College London (GB)
- Karolinska Institutet (SE)
- Icahn School of Medicine at Mount Sinai (US)
- University of Helsinki (FI)
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Singh, Tarjinder
- Barrett, Jeffrey C
- ORCID
- Singh, Tarjinder
- Walters, James T R
- Johnstone, Mandy
- Curtis, David
- Suvisaari, Jaana
- Rees, Elliott
- Iyegbe, Conrad
- Blackwood, Douglas
- McIntosh, Andrew M
- Geschwind, Daniel
- Murray, Robin M
- Bramon, Elvira
- Gandal, Michael
- Hultman, Christina M
- Sklar, Pamela
- Palotie, Aarno
- Sullivan, Patrick F
- O'Donovan, Michael C
- Owen, Michael J
- Barrett, Jeffrey C
- Venue
- Nature Genetics
- Published
- 2017-06-26
- Volume
- 49
- Issue
- 8
- Pages
- 1167-1173
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5533219
- OpenAlex
- W2626497039
- Cited by
- 231
- References
- 56
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 16 · 2023: 26 · 2022: 30 · 2021: 30 · 2020: 35 · 2019: 33 · 2018: 22 · 2017: 11
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Funders
- Williams College
- University of Pennsylvania
- Johns Hopkins University (HHSN268200782096C)
- NHS Blood and Transplant
- Wellcome Trust (085475/Z/08/Z, 085475, 075491, UK10K, WT 098051, 100135, 072894, 075491/Z/04,, 090532, 085475/B/08/Z, WT091310, 090532/Z/09/Z, 090532/Z/09/)
- Broad Institute
- National Institute for Health and Care Research (R01 MH077139, PDA/02/06/016)
- British Heart Foundation (090532/Z/09/Z, G0800270, SP/09/002, RG/13/13/30194)
- Cardiff University (G0800509)
- Vetenskapsrådet (R01 MH077139, D0886501)
- National Institutes of Health (075491/Z/04, HHSN268200782096C, CA089392)
- Stanley Center for Psychiatric Research, Broad Institute
- NIHR BioResource
- Medical Research Council (MR/M008436/1, G0801418, MR/P005748/1, MR/K026992/1, G0800270, MR/L010305/1, MC_PC_15018, G0800509, HHSN268200782096C)
- NIHR Cambridge Biomedical Research Centre
- National Institute of Mental Health (R01MH041953, R01MH077139, U01MH105666, R01MH083094, R01MH095034, MH077139)
- National Institute on Drug Abuse (P50DA019706)
- National Human Genome Research Institute (U01HG004446, HHSN268200782096C)
- National Eye Institute (R01EY020483)
- National Cancer Institute (P50CA097007, R01CA133996, P01CA089392, P50CA084724, P50CA093459)
- National Institute of Environmental Health Sciences (R01ES011740)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- schizophrenia, intellectual disability, rare coding variants, copy number variation, de novo mutations, genetic risk, neurodevelopmental disorders, loss-of-function intolerance, variant burden, exome sequencing, family trios
- MeSH terms
- Humans, Intellectual Disability, Mutation, Schizophrenia, Genetic Variation, Case-Control Studies, Sequence Analysis, DNA, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Exome, Genotyping Techniques, Neurodevelopmental Disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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