De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia
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Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n = 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.
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Rare variant overlaps exist in liability to schizophrenia, autism spectrum disorder, and developmental disorder.
“There are rare variant overlaps in liability to schizophrenia, autism spectrum disorder (ASD) and developmental disorder (DD)8,30,31.”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [8]
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Mapping genomic loci implicates genes and synaptic biology in schizophrenia
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- Authors
- GROUP Investigators, Rees, E., Han, J., Morgan, J., Carrera, N., Escott-Price, V., Pocklington, A. J., Duffield, M., Hall, L. S., Legge, S. E., Pardiñas, A. F., Richards, A. L., Roth, J., Lezheiko, T., Kondratyev, N., Kaleda, V., Golimbet, V., Parellada, M., González-Peñas, J., Arango, C., Gawlik, M., Kirov, G., Walters, J. T. R., Holmans, P., O’Donovan, M. C., & Owen, M. J.
- Affiliations
- Cardiff University (GB)
- University of Würzburg (DE)
- Mental Health Research Center of Russian Academy of Medical Sciences (RU)
- Hospital General Universitario Gregorio Marañón (ES)
- Corresponding author
- O’Donovan, Michael C.
- Owen, Michael J.
- ORCID
- Rees, Elliott
- Han, Jun
- Morgan, Joanne
- Carrera, Noa
- Escott-Price, Valentina
- Pocklington, Andrew J.
- Hall, Lynsey S.
- Legge, Sophie E.
- Pardiñas, Antonio F.
- Richards, Alexander L.
- Roth, Julian
- Kondratyev, Nikolay
- Parellada, Mara
- Arango, Celso
- Gawlik, Micha
- Kirov, George
- Walters, James T. R.
- Holmans, Peter
- O’Donovan, Michael C.
- Owen, Michael J.
- Venue
- Nature Neuroscience
- Published
- 2020-01-13
- Volume
- 23
- Issue
- 2
- Pages
- 179-184
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC7007300
- OpenAlex
- W2999521630
- Cited by
- 129
- References
- 45
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 17 · 2023: 25 · 2022: 26 · 2021: 24 · 2020: 17
- FWCI
- 16.78
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- Johns Hopkins University
- European Commission (279227, 241909)
- Cardiff University (MR/L010305/1, G0800509)
- Medical Research Council (MR/L023784/2, MR/P005748/1, MR/L010305/1, G0800509)
- 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, de novo mutations, SLC6A1, GABA transporters, missense mutations, loss-of-function intolerance, neurodevelopmental disorders, polygenic risk, bipolar disorder
- MeSH terms
- Exome Sequencing, Adult, Female, Humans, Male, Schizophrenia, Genetic Predisposition to Disease, Mutation, Missense, GABA Plasma Membrane Transport Proteins
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