Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

By Stephan J Sanders, Xin He, A. Willsey, A. Ercan-Sencicek, Kaitlin E. Samocha, A. E. Cicek, M. Murtha, V. Bal, S. Bishop, Shan Dong and 36 more. Neuron, 2015

1,391 citations recorded by the source corpus.

SUMMARY Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Subfields: Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/177d95d153942b4ed6c294bee863593e6bdf070d

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cognitive Neuroscience

In Genetics

Citations in the corpus

Psychiatric Genomics: An Update and an Agenda (2017, background): “Genetic causes of severe intellectual disability (32), autism spectrum disorder (33, 34), and schizophrenia (35) include copy number variants (CNVs), inherited known recessives, and single-nucleotide variants (SNVs).”
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, positive): “The ASD-associated isoform ANK2-013 has two additional interacting partners, SCN4B and TAF9.”
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2019, background): “Of the 15 102 ASD-associated genes, 60 were not discovered by our earlier analyses (De Rubeis et al., 16 2014; Sanders et al., 2015), including 31 that have not been implicated in autosomal dominant 17 neurodevelopmental disorders and were not significantly enriched for de novo and/or rare 18 varian”
Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016, neutral): “…with multiple gene sets from this RNA-seq study, post-mortem ASD cortex microarray 8 , human cortical development 10 , the set of all brain-expressed lncRNAs, genes enriched for ASD-associated rare variants 26 , and genes with de novo variants associated with intellectual disability (ID) 9 .”
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019, background): “Considerable genetic research has highlighted the importance of de novo mutations, copy number variations, and rare and common variants in ASD etiology (An et al., 2018; Gandal et al., 2018; Sanders et al., 2015; de la Torre-Ubieta et al., 2016), many of which have been modeled in animals (Patel et ”
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder (2017, positive): “Among these, 43 were found to be ASD-risk genes in a previous meta-analysis of exome sequencing 24 or in other CNV studies 10,15,17 .”
Predicting Splicing from Primary Sequence with Deep Learning. (2019, background): “21 conﬁrmed de novo cryptic splice mutations, we observed 9 cases of novel junction creation (Iossifov et al., 2014; Sanders et al., 2015), 8 cases of exon skipping, and 4 cases of intron retention, as well as more complex splicing aberrations (Figure 5F; Table S4).”