Characterization of SLITRK1 variation in obsessive-compulsive disorder
Open accessAbstract
Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P<0.05). In addition, we showed the the N400I variant failed to enhance neurite outgrowth in primary neuronal cultures, in contrast to wildtype SLITRK1, which enhanced neurite outgrowth in this assay. These important functional differences in the N400I variant, as compared to the wildtype SLITRK1 sequence, may contribute to OCD and OC spectrum symptoms. A synonymous L63L change identified in an individual with OCD and an additional missense change, T418S, was found in four individuals with OCD and in one individual without an OCD spectrum disorder. Examination of additional samples will help assess the role of rare SLITRK1 variation in OCD and in related psychiatric illness.
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There is an ancestral S330A mutation of SLITRK1 that may be involved in obsessive-compulsive disorders like Tourette's Syndrome.
“Among those mutations we found through an exhaustive literature review, there is an ancestral S330A mutation of SLITRK1 that may be involved in obsessive-compulsive disorders like Tourette’s Syndrome [116, 117].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [116]
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- Authors
- Ozomaro, U., Cai, G., Kajiwara, Y., Yoon, S., Makarov, V., Delorme, R., Betancur, C., Ruhrmann, S., Falkai, P., Grabe, H. J., Maier, W., Wagner, M., Lennertz, L., Moessner, R., Murphy, D. L., Buxbaum, J. D., Züchner, S., & Grice, D. E.
- Affiliations
- University of Miami (US)
- Icahn School of Medicine at Mount Sinai (US)
- Institut Pasteur (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Cologne (DE)
- Universitätsmedizin Greifswald (DE)
- University of Bonn (DE)
- National Institutes of Health (US)
- Corresponding author
- Grice, Dorothy E.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-08-21
- Volume
- 8
- Issue
- 8
- Pages
- e70376
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3749144
- OpenAlex
- W2090505689
- Cited by
- 52
- References
- 25
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 4 · 2020: 2 · 2019: 8 · 2018: 5 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 5
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Beatrice and Samuel A. Seaver Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Mental Health (F31MH086275)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- obsessive-compulsive disorder, SLITRK1, rare variants, missense mutations, neurite outgrowth, synonymous mutations, Tourette syndrome, trichotillomania, mutational burden, genetic risk
- MeSH terms
- Adult, Amino Acid Sequence, Animals, Mental Disorders, Brain, Child, Female, Tourette Syndrome, Humans, Male, Membrane Proteins, Middle Aged, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Obsessive-Compulsive Disorder, Phenotype, Genetic Variation, Case-Control Studies, Neurites, Sequence Homology, Amino Acid, Mutation, Missense, Mice
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