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시냅스뇌질환연구단
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Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder

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Title
Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder
Author(s)
Kim, Jae Hyun; Koh, In Gyeong; Lee, Hyeji; Lee, Gang-Hee; Song, Da-Yea; Kim, Soo-Whee; Kim, Yujin; Han, Jae Hyun; Bong, Guiyoung; Lee, Jeewon; Byun, Heejung; Son, Ji Hyun; Kim, Ye Rim; Lee, Yoojeong; Kim, Justine Jaewon; Park, Jung Woo; Kim, Il Bin; Choi, Jung Kyoon; Jang, Ja-Hyun; Trost, Brett; Lee, Junehawk; Eunjoon Kim; Yoo, Hee Jeong; An, Joon-Yong
Publication Date
2024-07
Journal
Psychiatry and Clinical Neurosciences, v.78, no.7, pp.405 - 415
Publisher
Blackwell Publishing Inc.
Abstract
Aim: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. Methods: We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci. Results: In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers. Conclusion: Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population. © 2024 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.
URI
https://pr.ibs.re.kr/handle/8788114/15311
DOI
10.1111/pcn.13676
ISSN
1323-1316
Appears in Collections:
Center for Synaptic Brain Dysfunctions(시냅스 뇌질환 연구단) > 1. Journal Papers (저널논문)
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