Combining multivariate genomic approaches to elucidate the comorbidity between ASD and ADHD

Peyre, Hugo; Schoeler, Tabea; Liu, Chao-Yu; Williams, Camille Michèle; Hoertel, Nicolas; Havdah, Alexandra; Pingault, Jean‐Baptiste

doi:10.1101/2020.04.22.054825

Cited by 4 publications

(3 citation statements)

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“…The extensive involvement of XRN2 in such complex mechanisms of gene expression regulation, particularly in neuronal cell types, offer possible insights into the vast heterogeneity of ASD and its overlap with other neurodevelopmental disorders. In fact, more recent research efforts have focused on ascertaining genetic commonalities between ASD and related disorders such as ADHD, obsessive compulsive disorder (OCD), and Tourette Syndrome, of which XRN2 seems to be a shared significant locus (Peyre et al 2020;Yang et al 2021).…”

Section: Discussionmentioning

confidence: 99%

SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

Gonzales

Zhao

Choi

et al. 2023

Preprint

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Background: Genome-wide association studies and next generation sequencing data analyses based on DNA information have identified thousands of mutations associated with autism spectrum disorder (ASD). However, more than 99% of identified mutations are non-coding. Thus, it is unclear which of these mutations might be functional and thus potentially causal variants. Transcriptomic profiling using total RNA-sequencing has been one of the most utilized approaches to link protein levels to genetic information at the molecular level. The transcriptome captures molecular genomic complexity that the DNA sequence solely does not. Some mutations alter a gene's DNA sequence but do not necessarily change expression and/or protein function. To date, few common variants reliably associated with the diagnosis status of ASD despite consistently high estimates of heritability. In addition, reliable biomarkers used to diagnose ASD or molecular mechanisms to define the severity of ASD do not exist. Objectives: It is necessary to integrate DNA and RNA testing together to identify true causal genes and propose useful biomarkers for ASD. Methods: We performed gene-based association studies with adaptive test using genome-wide association studies (GWAS) summary statistics with two large GWAS datasets (ASD 2019 data: 18,382 ASD cases and 27,969 controls [discovery data]; ASD 2017 data: 6,197 ASD cases and 7,377 controls [replication data]) which were obtained from the Psychiatric Genomics Consortium (PGC). In addition, we investigated differential expression for genes identified in gene-based GWAS with a RNA-seq dataset (GSE30573: 3 cases and 3 controls) using the DESeq2 package. Results: We identified 5 genes significantly associated with ASD in ASD 2019 data (KIZ-AS1, p=8.67x10-10; KIZ, p=1.16x10-9; XRN2, p=7.73x10-9; SOX7, p=2.22x10-7; PINX1-DT, p=2.14x10-6). Among these 5 genes, gene SOX7 (p=0.00087), LOC101929229 (p=0.009), and KIZ-AS1 (p=0.059) were replicated in ASD 2017 data. KIZ (p=0.06) was close to the boundary of replication in ASD 2017 data. Genes SOX7 (p=0.0017, adjusted p=0.0085), LOC101929229 (also known as PINX1-DT, p=5.83x10-7, adjusted p=1.18x10-5), and KIZ (p=0.00099, adjusted p=0.0055) indicated significant expression differences between cases and controls in the RNA-seq data. SOX7 encodes a member of the SOX (SRY-related HMG-box) family of transcription factors pivotally contributing to determining of the cell fate and identity in many lineages. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins leading to autism. Conclusion: Gene SOX7 in the transcription factor family could be associated with ASD. This finding may provide new diagnostic and therapeutic strategies for ASD.

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Section: Discussionmentioning

confidence: 99%

SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

Gonzales

Zhao

Choi

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The extensive involvement of XRN2 in such complex mechanisms of gene expression regulation, particularly in neuronal cell types, offers possible insights into the vast heterogeneity of ASD and its overlap with other neurodevelopmental conditions. In fact, more recent research efforts have focused on ascertaining genetic commonalities between ASD and related disorders such as ADHD, obsessive compulsive disorder (OCD), and Tourette syndrome, of which XRN2 seems to be a shared significant locus ( Peyre et al, 2020 ; Yang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

Gonzales,

Zhao,

Choi

et al. 2023

Preprint

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Background Despite thousands of variants identified by genome-wide association studies (GWAS) to be associated with autism spectrum disorder (ASD), it is unclear which mutations are causal because most are noncoding. Consequently, reliable diagnostic biomarkers are lacking. RNA-seq analysis captures biomolecular complexity that GWAS cannot by considering transcriptomic patterns. Therefore, integrating DNA and RNA testing may reveal causal genes and useful biomarkers for ASD. Methods We performed gene-based association studies using an adaptive test method with GWAS summary statistics from two large Psychiatric Genomics Consortium (PGC) datasets (ASD2019: 18,382 cases and 27,969 controls; ASD2017: 6,197 cases and 7,377 controls). We also investigated differential expression for genes identified with the adaptive test using an RNA-seq dataset (GSE30573: 3 cases and 3 controls) and DESeq2. Results We identified 5 genes significantly associated with ASD in ASD2019 (KIZ-AS1, p = 8.67×10− 10; KIZ, p = 1.16×10− 9; XRN2, p = 7.73×10− 9; SOX7, p = 2.22×10− 7; LOC101929229 (also known as PINX1-DT), p = 2.14×10− 6). Two of the five genes were replicated in ASD2017: SOX7 (p = 0.00087) and LOC101929229 (p = 0.009), and KIZ was close to the replication boundary of replication (p = 0.06). We identified significant expression differences for SOX7 (p = 0.0017, adjusted p = 0.0085), LOC101929229 (p = 5.83×10− 7, adjusted p = 1.18×10− 5), and KIZ (p = 0.00099, adjusted p = 0.0055). SOX7 encodes a transcription factor that regulates developmental pathways, alterations in which may contribute to ASD. Limitations: The limitation of the gene-based analysis is the reliance on a reference population for estimating linkage disequilibrium between variants. The similarity of this reference population to the population of study is crucial to the accuracy of many gene-based analyses, including those performed in this study. As a result, the extent of our findings is limited to European populations, as this was our reference of choice. Future work includes a tighter integration of DNA and RNA information as well as extensions to non-European populations that have been under-researched. Conclusions These findings suggest that SOX7 and its related SOX family genes encode transcription factors that are critical to the downregulation of the canonical Wnt/\(\beta\)-catenin signaling pathway, an important developmental signaling pathway, providing credence to the biologic plausibility of the association between gene SOX7 and autism spectrum disorder.

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“…This pattern of findings likely reflects the well-reported genetic overlap between different psychopathologies. New methods are being developed to differentiate shared and specific genetic variance across multiple psychopathologies (e.g., genomic structural equation modeling: Grotzinger et al, 2019;Peyre et al, 2021). To some extent, this pattern may also reflect symptom overlap between current diagnostic categories.…”

Section: Polygenic Risk Scoresmentioning

confidence: 99%

Using genetic designs to identify likely causal environmental contributions to psychopathology

Sellers

Riglin²,

Harold³

et al. 2022

Dev Psychopathol

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The multifactorial nature of psychopathology, whereby both genetic and environmental factors contribute risk, has long been established. In this paper, we provide an update on genetically informative designs that are utilized to disentangle genetic and environmental contributions to psychopathology. We provide a brief reminder of quantitative behavioral genetic research designs that have been used to identify potentially causal environmental processes, accounting for genetic contributions. We also provide an overview of recent molecular genetic approaches that utilize genome-wide association study data which are increasingly being applied to questions relevant to psychopathology research. While genetically informative designs typically have been applied to investigate the origins of psychopathology, we highlight how these approaches can also be used to elucidate potential causal environmental processes that contribute to developmental course and outcomes. We highlight the need to use genetically sensitive designs that align with intervention and prevention science efforts, by considering strengths-based environments to investigate how positive environments can mitigate risk and promote children’s strengths.

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Combining multivariate genomic approaches to elucidate the comorbidity between ASD and ADHD

Cited by 4 publications

References 60 publications

SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

SOX7: Novel Autistic Gene Identified by Analysis of Multi-Omics Data

Using genetic designs to identify likely causal environmental contributions to psychopathology

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