Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals
Open accessAbstract
The oxytocin receptor (OXTR) gene has been implicated as a risk gene for autism spectrum disorder (ASD)—a neurodevelopmental disorder with essential features of impairments in social communication and reciprocal interaction. The genetic associations between common variations in OXTR and ASD have been reported in multiple ethnic populations. However, little is known about the distribution of rare variations within OXTR in ASD patients. In this study, we resequenced the full length of OXTR in 105 ASD individuals using an approach that combined the power of next-generation sequencing technology, long-range PCR and DNA pooling. We demonstrated that rare variants with minor allele frequency as low as 0.05% could be reliably detected by our method. We identified 28 novel variants including potential functional variants in the intron region and one rare missense variant (R150S). We subsequently performed Sanger sequencing and validated five novel variants located in previously suggested candidate regions in ASD individuals. Further sequencing of 312 healthy subjects showed that the burden of rare variants is significantly higher in ASDs compared with healthy individuals. Our results support that the rare variation in OXTR gene might be involved in ASD. People harboring rare variants in the receptor gene for the hormone oxytocin may be at higher risk of autism spectrum disorder (ASD). Oxytocin is synthesized in the brain, and recent studies indicate it plays a vital role in social behaviors. For this reason, the dysfunction of the oxytocin receptor gene (OXTR) has been implicated in the development of ASD. Katsushi Tokunaga and Tsukasa Sasaki at the University of Tokyo, with scientists across Japan, have developed a method for pinpointing rare OXTR variants. This highly sensitive method, incorporating next-generation sequencing, enabled the team to uncover 28 novel variants in 105 ASD sufferers. They further examined top candidate regions of OXTR in additional 312 healthy individuals, and found ASD individuals carries a higher burden of rare variants compared with the healthy individuals. Further research with a larger sample size is needed.
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The sequence containing NT213739 overlapped peaks of DNase hypersensitivity and CTCF binding within the large intron, a region proposed to contain cis-regulatory elements in humans.
“The sequence containing NT213739 overlapped peaks of DNase hypersensitivity and CTCF binding within the large intron, a region proposed to contain cis-REs in humans (20, 61, 62).”
From Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment (2016) · cites this paper as [61]
The human OXTR intron may contain additional cis-regulatory elements.
“Additionally, the human intron may contain other cis-REs (61)”
From Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment (2016) · cites this paper as [61]
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“In the human OXTR third intron, the CTCF peak is found near a SNP, rs237887, that was predicted to be near a cis-RE and associated with face recognition abilities (20) and ASD diagnosis (21).”
Influential
- Authors
- Liu, X., Kawashima, M., Miyagawa, T., Otowa, T., Latt, K. Z., Thiri, M., Nishida, H., Sugiyama, T., Tsurusaki, Y., Matsumoto, N., Mabuchi, A., Tokunaga, K., & Sasaki, T.
- Affiliations
- The University of Tokyo (JP)
- Japan Science and Technology Agency (JP)
- Hamamatsu University (JP)
- Yokohama City University (JP)
- Corresponding author
- Tokunaga, Katsushi
- Sasaki, Tsukasa
- ORCID
- Venue
- Human Genome Variation
- Published
- 2015-07-30
- Volume
- 2
- Issue
- 1
- Pages
- 15024-15024
- ISSN
- 2054-345X (ISSN-L)
- PMC
- PMC4785550
- OpenAlex
- W2336763512
- Cited by
- 18
- References
- 35
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2019: 2 · 2017: 6 · 2016: 2 · 2015: 1
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-01-14)
- Open access
- gold
- doi.org
- Licence
- Locations
- Human Genome Variation (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Tokyo
- Japan Society for the Promotion of Science (26461712, 21300242, 15H04709, 25461723, 25893290)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- oxytocin receptor, autism spectrum disorder, rare variants, novel variants, intronic variants, genetic burden, candidate regions, DNA pooling, long-range PCR, next-generation sequencing
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