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Psychiatry Clin. Neurosci., 15 May 2024 | https://doi.org/10.1111/pcn.13676 Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder

Jae Hyun Kim, BSc,^1,2 In Gyeong Koh, BSc,^1,2 Hyeji Lee, BSc,^1,2 Gang-Hee Lee, BSc,^1,2 Da-Yea Song, MHS,^3,4 Soo-Whee Kim, BSc,^1,2 Yujin Kim, BSc,^1,2 Jae Hyun Han, MD, MS,^3,5 Guiyoung Bong, MA,⁴ Jeewon Lee, MD, PhD,⁶ Heejung Byun, MD, PhD,⁷ Ji Hyun Son, MD, PhD,⁷ Ye Rim Kim, MD,^3,4 Yoojeong Lee, MD, PhD,³Justine Jaewon Kim, MA,³ Jung Woo Park, PhD,⁸ Il Bin Kim, MD, PhD,⁹ Jung Kyoon Choi, PhD,¹⁰ Ja-Hyun Jang, MD, PhD,¹¹ Brett Trost, PhD,^12,13 Junehawk Lee, PhD,⁸ Eunjoon Kim, PhD,^14,15 Hee Jeong Yoo, MD, PhD^3,4* and Joon-Yong An, PhD^1,2,16*

¹Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea

²L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea

³Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

⁴Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea

⁵Department of Psychiatry, College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea

⁶Department of Psychiatry, Soonchunhyang University College of Medicine, Asan, Republic of Korea

⁷Department of Neuropsychiatry, Seoul Metropolitan Children’s Hospital, Seoul, Republic of Korea

⁸Center for Biomedical Computing, Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon, Republic of Korea

⁹Department of Psychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea

¹⁰Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

¹¹Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

¹²Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada

¹³Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada

¹⁴Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, Republic of Korea

¹⁵Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

¹⁶School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea

^*Correspondence: Hee Jeong Yoo MD, PhD, Joon-Yong An PhD

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.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-16)
연구진국내 연구진
분야 생명과학 > 유전학

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