Association of genetic variants with autism spectrum disorder in Japanese children revealed by targeted sequencing

Yuka Shiota; Tomoaki Nishiyama; Shigeru Yokoyama; Yuko Yoshimura; Chiaki Hasegawa; Sanae Tanaka; Sumie Iwasaki; Mitsuru Kikuchi

doi:10.3389/fgene.2024.1352480

Association of genetic variants with autism spectrum disorder in Japanese children revealed by targeted sequencing

Front Genet. 2024 Aug 30:15:1352480. doi: 10.3389/fgene.2024.1352480. eCollection 2024.

Authors

Yuka Shiota^{1

2}, Tomoaki Nishiyama³, Shigeru Yokoyama^{2

4}, Yuko Yoshimura^{4

5}, Chiaki Hasegawa^{2

4}, Sanae Tanaka^{2

4}, Sumie Iwasaki^{1

5}, Mitsuru Kikuchi^{4

6}

Affiliations

¹ Japan Society for the Promotion of Science, Tokyo, Japan.
² Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan.
³ Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan.
⁴ United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University, and University of Fukui, Kanazawa, Japan.
⁵ Institute of Human and Social Sciences, Kanazawa University, Kanazawa, Japan.
⁶ Department of Psychiatry and Neurobiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

Abstract

Introduction: Autism spectrum disorders (ASD) represent a heterogeneous group of neurodevelopmental disorders with strong genetic predispositions. Although an increasing number of genetic variants have been implicated in the pathogenesis of ASD, little is known about the relationship between ASD-associated genetic variants and individual ASD traits. Therefore, we aimed to investigate these relationships.

Methods: Here, we report a case-control association study of 32 Japanese children with ASD (mainly with high-functioning autism [HFA]) and 36 with typical development (TD). We explored previously established ASD-associated genes using a next-generation sequencing panel and determined the association between Social Responsiveness Scale (SRS) T-scores and intelligence quotient (IQ) scores.

Results: In the genotype-phenotype analyses, 40 variants of five genes (SCN1A, SHANK3, DYRK1A, CADPS, and SCN2A) were associated with ASD/TD phenotypes. In particular, 10 SCN1A variants passed permutation filtering (false discovery rate <0.05). In the quantitative association analyses, 49 variants of 12 genes (CHD8, SCN1A, SLC6A1, KMT5B, CNTNAP2, KCNQ3, SCN2A, ARID1B, SHANK3, DYRK1A, FOXP1, and GRIN2B) and 50 variants of 10 genes (DYRK1A, SCN2A, SLC6A1, ARID1B, CNTNAP2, SHANK3, FOXP1, PTEN, SCN1A, and CHD8) were associated with SRS T- and IQ-scores, respectively.

Conclusion: Our data suggest that these identified variants are essential for the genetic architecture of HFA.

Keywords: autism spectrum disorder; common variant; genetic architecture; high-functioning autism; next-generation sequencing; single-nucleotide polymorphism; social responsiveness scale.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by Grant-in-Aid for JSPS Fellows (grant Number: 22J14602) and Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics. Furthermore, the work was partially supported by the Moonshot Research and Development Program (grant number: JPMJMS2297) from Japan Science and Technology Agency, JST, and the Collaborative Research Program of the Collaborative Research Network for Asian Children with Developmental Disorders: MEXT Policy Initiative FY 2021, under joint research conducted through the initiative.