Rare coding variation illuminates the allelic architecture, risk genes, cellular expression patterns, and phenotypic context of autism

Abstract

Individuals with autism spectrum disorder (ASD) or related neurodevelopmental disorders (NDDs) often carry disruptive mutations in genes that are depleted of functional variation in the broader population. We build upon this observation and exome sequencing from 154,842 individuals to explore the allelic diversity of rare protein-coding variation contributing risk for ASD and related NDDs. Using an integrative statistical model, we jointly analyzed rare protein-truncating variants (PTVs), damaging missense variants, and copy number variants (CNVs) derived from exome sequencing of 63,237 individuals from ASD cohorts. We discovered 71 genes associated with ASD at a false discovery rate (FDR) ≤ 0.001, a threshold approximately equivalent to exome-wide significance, and 183 genes at FDR ≤ 0.05. Associations were predominantly driven by de novo PTVs, damaging missense variants, and CNVs: 57.4%, 21.2%, and 8.32% of evidence, respectively. Though fewer in number, CNVs conferred greater relative risk than PTVs, and repeat-mediated de novo CNVs exhibited strong maternal bias in parent-of-origin (e.g., 92.3% of 16p11.2 CNVs), whereas all other CNVs showed a paternal bias. To explore how genes associated with ASD and NDD overlap or differ, we analyzed our ASD cohort alongside a developmental delay (DD) cohort from the deciphering developmental disorders study (DDD; n=91,605 samples). We first reanalyzed the DDD dataset using the same models as the ASD cohorts, then performed joint analyses of both cohorts and identified 373 genes contributing to NDD risk at FDR ≤ 0.001 and 662 NDD risk genes at FDR ≤ 0.05. Of these NDD risk genes, 54 genes (125 genes at FDR ≤ 0.05) were unique to the joint analyses and not significant in either cohort alone. Our results confirm overlap of most ASD and DD risk genes, although many differ significantly in frequency of mutation. Analyses of single-cell transcriptome datasets showed that genes associated predominantly with DD were strongly enriched for earlier neurodevelopmental cell types, whereas genes displaying stronger evidence for association in ASD cohorts were more enriched for maturing neurons. The ASD risk genes were also enriched for genes associated with schizophrenia from a separate rare coding variant analysis of 121,570 individuals, emphasizing that these neuropsychiatric disorders share common pathways to risk.

Balanced chromosomal rearrangements offer insights into coding and noncoding genomic features associated with developmental disorders

“…Haploinsufficiency of TCF4 is the dominant genetic cause of Pitt-Hopkins Syndrome and has been associated with autism spectrum disorder (ASD) and broadly defined neurodevelopmental disorders (NDDs). 43,44 The three remaining protein-coding genes did not reach exome-wide significance but had suggestive ( P ≤ 0.005) evidence of association with DDs in our analyses. These included two established DD genes ( AUTS2, MBD5 ) 45,46 and one candidate DD gene, CDK6 , which was disrupted in three cases that presented with developmental delay ( n = 3), speech delay ( n = 2), microcephaly ( n = 2), and cardiac defects ( n = 1).…”

“…Haploinsufficiency of TCF4 is the dominant genetic cause of Pitt-Hopkins Syndrome and has been associated with autism spectrum disorder (ASD) and broadly defined neurodevelopmental disorders (NDDs). 43,44 The three remaining protein-coding genes…”

Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models

“…D. DEG enrichment for gene sets and modules previously published with functional associations with neurological phenotype, synaptic activity, and MEF2C function. Mouse Model RNAseq DEG Validation: Harrington et al, eLife, 2016 40 ; Biological Processes Gene Sets: GSEA msigDB 46,47 , Synaptic genes: Syngo v1.1; MEF2C targets: ENCODE LCL ChIPseq 48 ; TF Binding Motif-associated Gene Sets: GSEA msigDB 46,47 ; LoF constrained: gnomAD 49 ; NDD: Neurodevelopmental Disorder-associated genes, Fu, et al medRxiv 22 ; DNA Binding and Transcription Modules (‡): Parikshak et al, Cell, 2013 41 ; Synaptic Activity Modules (‡): Parikshak et al, Cell, 2013 41 ; Neuroepithelial Precursor and Neuron Expression Modules (§): Li et al, Science, 2018 42 .…”

Convergent coexpression of autism associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies

“…We next sought to leverage coexpression to test convergence of risk genes implicated from the most recent ASD exome sequencing study 5 . Among the 71 implicated genes, 70 had coexpression data and could be meta-analyzed to calculate the convergent coexpression.…”