The role of AUTS2 in neurodevelopment and human evolution

Oksenberg, Nir; Ahituv, Nadav

doi:10.1016/j.tig.2013.08.001

Cited by 129 publications

(129 citation statements)

References 76 publications

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“…Although there was no overlap between methylation of individual CpGs across all 4 NNNS outcomes, there was significant overlap at the gene level, suggesting that epigenetic patterning of these critical genes in different regions may influence multiple NNNS outcomes in a coordinated fashion. These overlapping genes included AUTS2, which is involved in neuronal development and linked to neurodevelopmental disorders, 50 and PCDHA, which traditionally localizes to synaptic junctions and is involved in neurogenesis, and is also implicated in neurodevelopmental disorders such as autism. 51 These genes were involved with molecular pathways involving cellular adhesion and nervous system development.…”

Section: Discussionmentioning

confidence: 99%

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior

et al. 2016

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(2016) Regions of variable DNA methylation in human placenta associated with newborn neurobehavior, Epigenetics, 11:8, 603-613, DOI: 10.1080/15592294.2016 ABSTRACTThe placenta regulates the in utero environment and functionally impacts fetal development. Candidate gene studies identified variation in placental DNA methylation is associated with newborn neurologic and behavioral outcomes including movement quality, lethargic behavior, attention, and arousal. We sought to identify novel regions of variable DNA methylation associated with newborn attention, lethargy, quality of movement, and arousal by performing an epigenome-wide association study in 335 infants from a US birth cohort. Methylation status was quantified using the Illumina HumanMethylation450 BeadChip array and associations to newborn outcomes assessed by the NICU Network Neurobehavioral Scales (NNNS) were identified while incorporating established bioinformatics algorithms to control for confounding by cell type composition. Methylation of CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) demonstrated genome-wide significance (P < 1.8 £ 10 ¡7 ) in specific associations with infant attention. CpGs whose differential methylation was associated with all 4 neurobehavioral outcomes were common to 50 genes involved in biological processes relating to cellular adhesion and nervous system development. Comprehensive methylation profiling identified relationships between methylation of FHIT and ANKRD11, which have been previously linked to neurodevelopment and behavioral outcomes in genetic association studies. Subtle changes in DNA methylation of these genes within the placenta may impact normal variation of a newborn's ability to alter and track visual and auditory stimuli. Gene ontology analysis suggested that those genes with variable methylation related to these outcomes are overrepresented in biological pathways involved in brain development and placental physiology, supportive of our hypothesis for a key role of the placenta in neurobehavioral outcomes.

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Section: Discussionmentioning

confidence: 99%

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior

et al. 2016

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“…AUTS2 expression in the brain has been confirmed to be associated with the alcohol preference in mice (Schumann et al 2011), whereas downregulating the expression of the Drosophila AUTS2 homologue dAUTS2/tay gene reduced the alcohol sensitivity of Drosophila (Schumann et al 2011). AUTS2 expression was found to be significantly associated with nicotine dependence, cannabis dependence, and antisocial personality disorder, whereas these small-scale studies need to be confirmed by larger cohorts (Philibert et al 2007;Oksenberg and Ahituv 2013). Chen et al recently confirmed that AUTS2 gene expression in lymphoblastoid cell lines (LCL) was significantly reduced in 124 male patients with heroin dependence compared with 116 healthy male controls (Chen et al 2013).…”

Section: Introductionmentioning

confidence: 97%

The Evidence for the Contribution of the Autism Susceptibility Candidate 2 (AUTS2) Gene in Heroin Dependence Susceptibility

et al. 2014

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The single-nucleotide polymorphisms (SNP) rs6943555 in autism susceptibility candidate 2 (AUTS2) has been reported to be significantly associated with alcohol consumption in Europeans. In this study, we identified the SNP in AUTS2 contributing to the genetic susceptibility to heroin dependence. The potential association between heroin dependence and 21 SNPs (rs2270162, rs2851510, rs513150, rs595681, rs210606, rs10237984, rs13228123, rs10235781, rs6969375, rs6943555, rs10251416, rs17141963, rs12669427, rs723340, rs2293507, rs2293508, rs6960426, rs9886351, rs2293501, rs10277450, rs1918425) of AUTS2 was examined in a Chinese Han population using the MassARRAY system. The participants included 426 patients with heroin dependence and 416 healthy controls. Single SNP association, haplotype association, and clinical phenotype association were analyzed. Single SNP association revealed that AA homozygotes of rs6943555 were significantly over-represented in the patients with heroin dependence compared with the control subjects (P=0.0019). The patients with heroin dependence had a significantly higher frequency of the A allele (P=0.0003, odd ratio (OR)=1.429, 95% confidence interval (CI)=1.175-1.738). Strong linkage disequilibrium (LD) was observed in five blocks (D'>0.9). In block 2, significantly more A-A haplotypes (P=0.006 after Bonferroni corrections) and significantly fewer T-A haplotypes (P=0.040) were found in the patients with heroin dependence. The genotype and clinical phenotype correlation study of the rs6943555 carriers showed that the amount of heroin self-injection was lower in the patients with the AA genotype relative to AT+TT genotypes (P<0.01). Our results confirmed that, in addition to heroin consumption, the SNP rs6943555 of AUTS2 may also play an important role in the etiology of heroin dependence.

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“…Reportedly, AUTS2 contributes to the differentiation of human embryonic stem cells into cardiomyocytes, as well as the following differentiation of cardiomyocytes into beating embryoid bodies. 23) AUTS2 is involved in the Notch signaling pathway, 24) which takes part in mammalian cardiac development and is related to human congenital heart defects like bicuspid aortic valve disease, ventricular septal defects, and calcification of the heart valves. Moreover, AUTS2 is a transcriptome signature of heart malformations, 10) and it is associated with supravalvular aortic stenosis.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis of Genes and MicroRNAs Associated With Atrioventricular Septal Defect in Down Syndrome Patients

Wang

Li²,

Song

et al. 2016

Int. Heart J.

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SummaryDown syndrome (DS) is a common chromosome 21 abnormality disease, leading to various health problems, especially atrioventricular septal defect (AVSD). Genes and microRNAs (miRNAs) associated with AVSD in DS patients still need in-depth study.Gene expression data (GSE34457) of 22 DS patients without congenital heart disease and 7 DS patients with AVSD were downloaded from Gene Expression Omnibus. After screening differentially expressed genes (DEGs) based on limma package in R (criteria: P < 0.05 and |log 2 fold change (FC)| > 0.5), pathway and functional enrichment analyses were performed using the online software DAVID (criterion: P < 0.05). The protein-protein interaction (PPI) networks of DEGs were constructed based on the online server STRING (criterion: combined score > 0.4). Next, miRNAs that targeted DEGs were predicted based on Webgestalt (criteria: P < 0.05 and target DEGs ≥ 2), and miRNA-DEG regulatory networks were visualized through Cytoscape.A total of 179 DEGs were identified. Next, 5 functions and 1 pathway were enriched by up-regulated DEGs, while 4 functions were enriched by down-regulated DEGs. Furthermore, miRNA-DEG regulatory networks were constructed. IL1B was the hub-gene of PPI networks, and AUTS2 and KIAA2022 were predicted to be targeted by miR-518a, miR518e, miR-518f, miR-528a, and miR-96.IL1B, IL12RB2, AUTS2, and KIAA2022 might participate in AVSD in DS patients, and AUTS2 and KIAA2022 might be targeted by miR-518a, miR-518e, miR-518f, miR-528a, and miR-96. The identified genes and miRNAs might provide a theoretical basis for understanding AVSD in DS patients. (Int Heart J 2016; 57: 490-495)

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The role of AUTS2 in neurodevelopment and human evolution

Cited by 129 publications

References 76 publications

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior

Regions of variable DNA methylation in human placenta associated with newborn neurobehavior

The Evidence for the Contribution of the Autism Susceptibility Candidate 2 (AUTS2) Gene in Heroin Dependence Susceptibility

Bioinformatic Analysis of Genes and MicroRNAs Associated With Atrioventricular Septal Defect in Down Syndrome Patients

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