Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility

Nawa, Yoshihiro; Kimura, Hiroki; Mori, Daisuke; Kato, Hidekazu; Toyama, Miho; Furuta, Sho; Yu, Yanjie; Ishizuka, Kanako; Kushima, Itaru; Aleksić, Branko; Arioka, Yuko; Morikawa, Mako; Okada, Takashi; Inada, Toshiya; Kaibuchi, Kozo; Ikeda, Masashi; Iwata, Nakao; Suzuki, Michio; Okahisa, Yuko; Egawa, Jun; Someya, Toshiyuki; Nishimura, Fumichika; Sasaki, Tsukasa; Ozaki, Norio

doi:10.1038/s41439-020-00125-7

Cited by 7 publications

(7 citation statements)

References 52 publications

(57 reference statements)

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“…Similarly, variants in GRIN2B , which codes for the NR2B subunit of N ‐methyl‐ d ‐aspartate (NMDA) receptors (Freunscht et al, 2013), have also been associated with ASD, SCZ and other psychiatric disorders (Freunscht et al, 2013). Emerging evidence suggests that other single nucleotide variants, including DAB1 (Nawa et al, 2020), YWHAZ (Torrico et al, 2020), and NRXN1 (Hu et al, 2019 10 [Epub 2019 May 28]; Ishizuka et al, 2020), may also be associated with both ASD and SCZ.…”

Section: Resultsmentioning

confidence: 99%

Autism spectrum disorder and schizophrenia: An updated conceptual review

2021

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Autism spectrum disorder (ASD) and schizophrenia (SCZ) are separate disorders, with distinct clinical profiles and natural histories. ASD, typically diagnosed in childhood, is characterized by restricted or repetitive interests or behaviors and impaired social communication, and it tends to have a stable course. SCZ, typically diagnosed in adolescence or adulthood, is characterized by hallucinations and delusions, and tends to be associated with declining function. However, youth with ASD are three to six times more likely to develop SCZ than their neurotypical counterparts, and increasingly, research has shown that ASD and SCZ converge at several levels. We conducted a systematic review of studies since 2013 relevant to understanding this convergence, and present here a narrative synthesis of key findings, which we have organized into four broad categories: symptoms and behavior, perception and cognition, biomarkers, and genetic and environmental risk. We then discuss opportunities for future research into the phenomenology and neurobiology of overlap between ASD and SCZ. Understanding this overlap will allow for researchers, and eventually clinicians, to understand the factors that may make a child with ASD vulnerable to developing SCZ. Lay Summary Autism spectrum disorder and schizophrenia are distinct diagnoses, but people with autism and people with schizophrena share several characteristics. We review recent studies that have examined these areas of overlap, and discuss the kinds of studies we will need to better understand how these disorders are related. Understanding this will be important to help us identify which autistic children are at risk of developing schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Autism spectrum disorder and schizophrenia: An updated conceptual review

2021

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“…We validated 22 of 23 (96%) Alu insertions and 6/7 (86%) L1 insertions, achieving a high validation rate of 93% (28/30). Validated insertions include a full-length de novo intronic L1 insertion in DAB1, a gene with a high probability of being loss-of-function intolerant (pLI = 0.981) [ 36 ] and a hypothesized ASD gene [ 21 , 30 ] implicated in regulating neuronal migration in development via the Reelin pathway in an isoform dependent manner [ 41 ]. We additionally validated an exonic Alu insertion in ASD gene CSDE1 [ 22 ] in an ASD proband (Fig.…”

Section: Resultsmentioning

confidence: 99%

Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder

et al. 2021

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Background Retrotransposons have been implicated as causes of Mendelian disease, but their role in autism spectrum disorder (ASD) has not been systematically defined, because they are only called with adequate sensitivity from whole genome sequencing (WGS) data and a large enough cohort for this analysis has only recently become available. Results We analyzed WGS data from a cohort of 2288 ASD families from the Simons Simplex Collection by establishing a scalable computational pipeline for retrotransposon insertion detection. We report 86,154 polymorphic retrotransposon insertions—including > 60% not previously reported—and 158 de novo retrotransposition events. The overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 117, and 206 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 21 births total. However, ASD cases showed more de novo L1 insertions than expected in ASD genes. Additionally, we observed exonic insertions in loss-of-function intolerant genes, including a likely pathogenic exonic insertion in CSDE1, only in ASD individuals. Conclusions These findings suggest a modest, but important, impact of intronic and exonic retrotransposon insertions in ASD, show the importance of WGS for their analysis, and highlight the utility of specific bioinformatic tools for high-throughput detection of retrotransposon insertions.

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“…We validated 22 of 23 (96%) Alu insertions and 6/7 (86%) L1 insertions, achieving a high validation rate of 93% (28/30). Validated insertions include a full-length de novo intronic L1 insertion in DAB1, a gene with a high probability of being loss-of-function intolerant (pLI=0.981) 54 and hypothesized ASD gene 53; 63 implicated in regulating neuronal migration in development via the Reelin pathway in an isoform dependent manner 64 . We additionally validated an exonic Alu insertion in ASD gene CSDE1 55 in an ASD proband (Figure 5A).…”

Section: Main Textmentioning

confidence: 99%

Whole-genome analysis ofde novoand polymorphic retrotransposon insertions in Autism Spectrum Disorder

Monroy

Chu

Dias

et al. 2021

Preprint

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Retrotransposons are dynamic forces in evolutionary genomics and have been implicated as causes of Mendelian disease and hereditary cancer, but their role in Autism Spectrum Disorder (ASD) has never been systematically defined. Here, we report 86,154 polymorphic retrotransposon insertions including >60% not previously reported and 158 de novo retrotransposition events identified in whole genome sequencing (WGS) data of 2,288 families with ASD from the Simons Simplex Collection (SSC). As expected, the overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 104, and 192 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 20 births total, while the location of transposon insertions differed between ASD and unaffected individuals. ASD cases showed more de novo L1 insertions than expected in ASD genes, and we also found de novo intronic retrotransposition events in known syndromic ASD genes in affected individuals but not in controls. Additionally, we observed exonic insertions in genes with a high probability of being loss-of-function intolerant, including a likely causative exonic insertion in CSDE1, only in ASD individuals. Although de novo retrotransposition occurs less frequently than single nucleotide and copy number variants, these findings suggest a modest, but important, impact of intronic and exonic retrotransposition mutations in ASD and highlight the utility of developing specific bioinformatic tools for high-throughput detection of transposable element insertions.

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Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility

Cited by 7 publications

References 52 publications

Autism spectrum disorder and schizophrenia: An updated conceptual review

Autism spectrum disorder and schizophrenia: An updated conceptual review

Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder

Whole-genome analysis ofde novoand polymorphic retrotransposon insertions in Autism Spectrum Disorder

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