Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

By D. Pinto, Elsa Delaby, Daniele Merico, M. Barbosa, Alison K. Merikangas, L. Klei, B. Thiruvahindrapuram, Xiao Xu, R. Ziman, Zhuozhi Wang and 102 more. American Journal of Human Genetics, 2014

930 citations recorded by the source corpus.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10−5) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10−15, ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Subfields: Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/243b54688dac51ccb4b409e63029323c9858f738

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Citations in the corpus

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder (2017, positive): “Regarding genotypic heterogeneity, using established criteria 17,47 , in this study we were able to resolve a molecular basis in 11.2% of ASD cases; this tally should rise as we acquire more rare variant data to compare against 22 .”
The Changing Epidemiology of Autism Spectrum Disorders (2016, background): “Analysis of rare variants linked to ASD has revealed three common biological pathways—chromatin remodeling, synaptic cell adhesion and scaffolding, and neuronal signaling and development (18, 142).”
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci (2015, methodology): “Including additional dnCNV data (Levy et al., 2011; Pinto et al., 2014) identifies an additional two loci: deletions at NRXN1 and deletions and duplications at 22q11.”
Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder (2016, background): “( e ) Members of major ASD-associated pathways and complexes (Wnt signaling, MAPK signaling, and the postsynaptic density complex) showed similar significant enrichments.”
A highly conserved program of neuronal microexons is misregulated in autistic brains (2014, background): “(Pinto et al., 2014)) whereas partially shaded nodes are genes associated with intellectual disability, FMRP (fragile X mental retardation) or within an ASD CNV but not, as yet, directly implicated in ASD (Banerjee-Basu and Packer, 2010; Pinto et al.”
Sex/Gender Differences and Autism: Setting the Scene for Future Research (2015, background): “represented among individuals carrying exonic deletions overlapping fragile X syndrome protein targets.(94) An increased rate of mutation in females is also found in other neurodevelopmental disorders.”
Most genetic risk for autism resides with common variation (2014, background): “interval = 31–69%) and (8) total narrow-sense heritability due to both common and rare variation using smoothed estimates of relatedness (95%”