Both rare and common genetic variants contribute to autism in the Faroe Islands

Leblond, Claire S.; Cliquet, Freddy; Carton, Coralie; Huguet, Guillaume; Mathieu, Alexandre; Kergrohen, Thomas; Buratti, Julien; Lemière, Nathalie; Cuisset, Laurence; Bienvenu, Thierry; Boland, Anne; Deleuze, Jean‐François; Stórá, Tormóður; Biskupstoe, Rannva; Halling, Jonrith; Andorsdóttir, Guðrið; Billstedt, Eva; Gillberg, Christopher; Bourgeron, Thomas

doi:10.1101/363853

Cited by 2 publications

(2 citation statements)

References 72 publications

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“…For the Hip‐adult group, there are 12 hub genes identified, including Kdr , S1pr1 , Ubc , Grm2 , Grin2b , Nrxn1 , Pdyn , Grin3a , Itgam , Grin2a , Gabra2 , and Camk4 . Among them, Grin2b , Nrxn1 , Grin2a , Gabra2 , and Camk4 have been associated with ASD based on human genetics evidence, indicating that this integrated analysis indeed enriched genes that are important for ASD [Gonzalez‐Nunez, ; Leblond et al, ; Tarabeux et al, ; Zech et al, ]. Moreover, the other genes including Kdr , S1pr1 , Ubc , Grm2 , Pdyn , and Itgam are possible candidates for ASD due to the related molecular functions.…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

et al. 2019

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Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA‐Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein–protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex‐Adult subgroup, Gria1 in the Cortex‐Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus‐Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352–368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Abnormal transcriptional regulation accounts for a significant portion of Autism Spectrum Disorder. In this study, we performed transcriptome analyses of mouse models to identify common downstream targets of transcriptional regulators involved in ASD. We identified several recurrent target genes that are close related to the common pathological process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRM2, NRXN1, GRIN3A, ITGAM, GRIN2A, GABRA2, and CAMK4. These results provide potentially important targets for understanding the molecular mechanism of ASD.

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Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

et al. 2019

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“…Among the five genes intersected by rare loss events, RIMS2 was also intersected by a rare gain found in another individual of the ASD cohort. No study so far has reported the association of RIMS2 with genetic disorders, but its homologues RIMS3 and RIMS4 were implicated autism risk factors (Kumar et al, 2010; Leblond et al, 2018). RIMS2 codes for a presynaptic protein regulating synaptic membrane exocytosis, and mediates neurotransmitter release during short- and long-term synaptic plasticity (Kaeser and Südhof, 2005).…”

Section: Discussionmentioning

confidence: 99%

Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder

Fan

Liu

et al. 2018

Front. Genet.

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Autism spectrum disorder (ASD) is heterogeneous in symptom and etiology. Rare copy number variations (CNVs) are important genetic factors contributing to ASD. Currently chromosomal microarray (CMA) detecting CNVs is recommended as a first-tier diagnostic assay, largely based on research in North America and Europe. The feature of rare CNVs has not been well characterized in ASD cohorts from non-European ancestry. In this study, high resolution CMA was utilized to investigate rare CNVs in a Chinese cohort of ASD (n = 401, including 177 mildly/moderately and 224 severely affected individuals), together with an ancestry-matched control cohort (n = 197). Diagnostic yield was about 4.2%, with 17 clinically significant CNVs identified in ASD individuals, of which 12 CNVs overlapped with recurrent autism risk loci or genes. Autosomal rare CNV burden analysis showed an overrepresentation of rare loss events in ASD cohort, whereas the rate of rare gain events correlated with the phenotypic severity. Further analysis showed rare losses disrupting genes highly intolerant of loss-of-function variants were enriched in the ASD cohort. Among these highly constrained genes disrupted by rare losses, RIMS2 is a promising candidate contributing to ASD risk. This pilot study evaluated clinical utility of CMA and the feature of rare CNVs in Chinese ASD, with candidate genes identified as potential risk factors.

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Both rare and common genetic variants contribute to autism in the Faroe Islands

Cited by 2 publications

References 72 publications

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder

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