Association Study Identifying a New Susceptibility Gene (AUTS2) for Schizophrenia

Bao, Zhenan; Xu, Yuehong; Wei, Shuguang; Fu, Deliang; Feng, Zufei; Guan, Fanglin; Zhu, Yan; Li, Shengbin

doi:10.3390/ijms151119406

Cited by 37 publications

(33 citation statements)

References 40 publications

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“…In addition, 24 exonic microdeletions were identified in the AUTS2 gene in individuals with various psychiatric disorders (Beunders et al, 2013). Moreover, very recent studies suggested that this gene is also associated with schizophrenia (Zhang et al, 2014;McCarthy et al, 2014). The wide spectrum of phenotypes observed in patients with AUTS2 mutations suggests that this gene is not associated with a specific type of ASD but with a broader range of psychiatric disorders, thus highlighting AUTS2 as a current gene of interest .…”

Section: Introductionmentioning

confidence: 96%

Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

Hori¹,

Nagai²,

Shan³

et al. 2014

Cell Reports

118

199

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Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Immunohistochemistry and fractionation studies show that AUTS2 localizes not only in nuclei, but also in the cytoplasm, including in the growth cones in the developing brain. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These findings suggest that cytoplasmic AUTS2 acts as a regulator of Rho family GTPases to contribute to brain development and give insight into the pathology of human psychiatric disorders with AUTS2 mutations.

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Section: Introductionmentioning

confidence: 96%

Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

Hori¹,

Nagai²,

Shan³

et al. 2014

Cell Reports

118

199

View full text Add to dashboard Cite

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“…Autism susceptibility candidate 2 (AUTS2) (also termed "activator of transcription and developmental regulator") located on human chromosome 7q11.22 has been initially identified as a possible ASD risk gene in a study that reported a de novo balanced translocation in monozygotic twin patients with ASDs (Sultana et al, 2002). Thereafter, structural variants that disrupt the AUTS2 locus have been identified in the patients with not only autism, but also other neuropathological conditions including intellectual disabilities (IDs), schizophrenia, attention deficit hyperactivity disorder (ADHD), dyslexia and epilepsy as well as brain malformation and craniofacial abnormalities (Amarillo et al, 2014;Bakkaloglu et al, 2008;Ben-David et al, 2011;Beunders et al, 2013;Elia et al, 2010;Hori and Hoshino, 2017;Jolley et al, 2013;Kalscheuer et al, 2007;Talkowski et al, 2012;Zhang et al, 2014). In addition, AUTS2 has been recently implicated as a potential gene in human-specific evolution .…”

Section: [Introduction]mentioning

confidence: 99%

AUTS2 regulation of synapses for proper synaptic inputs and social communication

Hori

Yamashiro

Nagai

et al. 2019

Preprint

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Impairments in synapse development are thought to cause numerous psychiatric disorders.Autism susceptibility candidate 2 (AUTS2) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse regulation remains unclear. In this study, we found that excitatory synapses were specifically increased in the Auts2-deficient primary cultured neurons as well as Auts2 mutant forebrains. Electrophysiological recordings and immunostaining showed increases in excitatory synaptic inputs as well as c-fos expression in Auts2 mutant brains, suggesting that an altered balance of excitatory and inhibitory inputs enhances brain excitability. Auts2 mutant mice exhibited autistic-like behaviors including impairments in social interaction and altered vocal communication. Together, these findings suggest that AUTS2 regulates excitatory synapse number to coordinate E/I balance in the brain, whose impairment may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.

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“…In these genes, only TAF13 and SETD1A were suggested as top genes in previous study (Fromer, et al, 2012;Nguyen, et al, 2017). In addition, AUTS2 (PP>0.8) was reported as a SCZ genes from a common variant based study (Zhang, et al, 2014). Using expression data, multiple genes of these genes were expressed in prenatal stages, but the signals were as not strong as those of CHD ( Figure S6).…”

Section: Sczmentioning

confidence: 86%

mTADA: a framework for analyzing de novo mutations in multiple traits

Dobbyn

Buxbaum

et al. 2018

Preprint

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Joint analysis of multiple traits can result in the identification of associations not found through the analysis of each trait in isolation. In addition, approaches that consider multiple traits can aid in the characterization of shared genetic etiology among those traits. In recent years, parentoffspring trio studies have reported an enrichment of de novo mutations (DNMs) in neuropsychiatric disorders. The analysis of DNM data in the context of neuropsychiatric disorders has implicated multiple putatively causal genes, and a number of reported genes are shared across disorders. However, a joint analysis method designed to integrate de novo mutation data from multiple studies has yet to be implemented. We here introduce multiple-trait TADA (mTADA) which jointly analyzes two traits using DNMs from non-overlapping family samples. mTADA uses two single-trait analysis data sets to estimate the proportion of overlapping risk genes, and reports genes shared between and specific to the relevant disorders. We applied mTADA to >13,000 trios for six disorders: schizophrenia (SCZ), autism spectrum disorder (ASD), developmental disorders (DD), intellectual disability (ID), epilepsy (EPI), and congenital heart disease (CHD). We report the proportion of overlapping risk genes and the specific risk genes shared for each pair of disorders. A total of 153 genes were found to be shared in at least one pair of disorders. The largest percentages of shared risk genes were observed for pairs of DD, ID, ASD, and CHD (>20%) whereas SCZ, CHD, and EPI did not show strong overlaps in risk gene set between them. Furthermore, mTADA identified additional SCZ, EPI and CHD risk genes through integration with DD de novo mutation data. For CHD, using DD information, 31 risk genes with posterior probabilities > 0.8 were identified, and 20 of these 31 genes were not in the list of known CHD genes. We find evidence that most significant CHD risk genes are strongly expressed in prenatal stages of the human genes. Finally, we validated our findings for CHD and EPI in independent cohorts comprising 1241 CHD trios, 226 CHD singletons and 197 EPI trios. Multiple novel risk genes identified by mTADA also had de novo mutations in these independent data sets. The joint analysis method introduced here, mTADA, is able to identify risk genes shared by two traits as well as additional risk genes not found through single-trait analysis only. A number of risk genes reported by mTADA are identified only through joint analysis, specifically when ASD, DD, or ID are one of the two traits examined. This suggests that novel genes for the trait or a new trait might converge to a coregene list of the three traits. Insights into top mTADA genesOverlapping genes between two traits Using a threshold PP>0.8, 153 genes were supported by the two-trait model in at least one pair ( E > 0.8, Table S2). Seven genes (ARID1B, GABRB3, KCNQ2, STXBP1, SYNGAP1, TLK2, POGZ, SCN2A) were observed for at least six pairs of disorders (Table 2). POGZ and SCN2A were present in eight pairs of ...

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Association Study Identifying a New Susceptibility Gene (AUTS2) for Schizophrenia

Cited by 37 publications

References 40 publications

Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

AUTS2 regulation of synapses for proper synaptic inputs and social communication

mTADA: a framework for analyzing de novo mutations in multiple traits

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