Dataset Information

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

ABSTRACT: We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

SUBMITTER: Ruzzo EK

PROVIDER: S-EPMC7102900 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

Ruzzo Elizabeth K EK Pérez-Cano Laura L Jung Jae-Yoon JY Wang Lee-Kai LK Kashef-Haghighi Dorna D Hartl Chris C Singh Chanpreet C Xu Jin J Hoekstra Jackson N JN Leventhal Olivia O Leppä Virpi M VM Gandal Michael J MJ Paskov Kelley K Stockham Nate N Polioudakis Damon D Lowe Jennifer K JK Prober David A DA Geschwind Daniel H DH Wall Dennis P DP

Cell 20190801 4

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskelet ...[more]

PMID: 31398340

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Project description:BackgroundBoth de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). This study aimed to use exome data to prioritize recessive inherited genes (RIGs) with biallelically inherited variants in autosomes or X-linked inherited variants in males and investigate the functional relationships between RIGs and genes with de novo variants (DNGs).MethodsWe used a bioinformatics pipeline to analyze whole-exome sequencing data from 1799 ASD quads (containing one proband, one unaffected sibling, and their parents) from the Simons Simplex Collection and prioritize candidate RIGs with rare biallelically inherited variants in autosomes or X-linked inherited variants in males. The relationships between RIGs and DNGs were characterized based on different genetic perspectives, including genetic variants, functional networks, and brain expression patterns.ResultsAmong the biallelically or hemizygous constrained genes that were expressed in the brain, ASD probands carried significantly more biallelically inherited protein-truncating variants (PTVs) in autosomes (p = 0.038) and X-linked inherited PTVs in males (p = 0.026) than those in unaffected siblings. We prioritized eight autosomal, and 13 X-linked candidate RIGs, including 11 genes already associated with neurodevelopmental disorders. In total, we detected biallelically inherited variants or X-linked inherited variants of these 21 candidate RIGs in 26 (1.4%) of 1799 probands. We then integrated previously reported known or candidate genes in ASD, ultimately obtaining 70 RIGs and 87 DNGs for analysis. We found that RIGs were less likely to carry multiple recessive inherited variants than DNGs were to carry multiple de novo variants. Additionally, RIGs and DNGs were significantly co-expressed and interacted with each other, forming a network enriched in known functional ASD clusters, although RIGs were less likely to be enriched in these functional clusters compared with DNGs. Furthermore, although RIGs and DNGs presented comparable expression patterns in the human brain, RIGs were less likely to be associated with prenatal brain regions, the middle cortical layers, and excitatory neurons than DNGs.LimitationsThe RIGs analyzed in this study require functional validation, and the results should be replicated in more patients with ASD.ConclusionsASD RIGs were functionally associated with DNGs; however, they exhibited higher heterogeneity than DNGs.

Dataset Information

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

Publications

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

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