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Cited by 145Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersBioinformatics and Genomic Networks

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Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders

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Ben-David, Eyal, Shifman, Sagiv·2012·PLoS Genetics
DOI 10.1371/journal.pgen.1002556PMC PMC3297570
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Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disorders with phenotypic and genetic heterogeneity. Recent studies have reported rare and de novo mutations in ASD, but the allelic architecture of ASD remains unclear. To assess the role of common and rare variations in ASD, we constructed a gene co-expression network based on a widespread survey of gene expression in the human brain. We identified modules associated with specific cell types and processes. By integrating known rare mutations and the results of an ASD genome-wide association study (GWAS), we identified two neuronal modules that are perturbed by both rare and common variations. These modules contain highly connected genes that are involved in synaptic and neuronal plasticity and that are expressed in areas associated with learning and memory and sensory perception. The enrichment of common risk variants was replicated in two additional samples which include both simplex and multiplex families. An analysis of the combined contribution of common variants in the neuronal modules revealed a polygenic component to the risk of ASD. The results of this study point toward contribution of minor and major perturbations in the two sub-networks of neuronal genes to ASD risk.

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Figure 1 Weighted gene co-expression network analysis (WGCNA) of human brain transcriptomes. (A) Color map showing the relative sizes of the different modules in the WGCNA analysis. Colors correspond to arbitrary names given to each module. (B) Enrichment for genes up-regulated in Neurons (left), Astrocytes (center) and Oligodendrocytes (right). For each module, the relative risk (RR) for harboring cell-type specific genes is plotted. Insets show the distribution of the rank of enriched genes located in modules with the highest cell-type specific RR. The distribution is shown for the Salmon, Magenta and Blue module for genes enriched in neurons, astrocytes, and oligodendrocytes (respectively). (C) Top connected genes in the Magenta module. Nodes are ordered and sized according to their degree. (D) Top connected genes in the Yellow module, revealing two distinct groups of genes. One group (left circle) includes genes involved in protein translation, and the other (right circle) includes Microglia specific genes.
Figure 1 Weighted gene co-expression network analysis (WGCNA) of human brain transcriptomes. (A) Color map showing the relative sizes of the different modules in the WGCNA analysis. Colors correspond to arbitrary names given to each module. (B) Enrichment for genes up-regulated in Neurons (left), Astrocytes (center) and Oligodendrocytes (right). For each module, the relative risk (RR) for harboring cell-type specific genes is plotted. Insets show the distribution of the rank of enriched genes located in modules with the highest cell-type specific RR. The distribution is shown for the Salmon, Magenta and Blue module for genes enriched in neurons, astrocytes, and oligodendrocytes (respectively). (C) Top connected genes in the Magenta module. Nodes are ordered and sized according to their degree. (D) Top connected genes in the Yellow module, revealing two distinct groups of genes. One group (left circle) includes genes involved in protein translation, and the other (right circle) includes Microglia specific genes.CC BY · PubMed Central
Figure 2 Modules correspond to specific neuronal sub-groups acting in specific regions. (A) For the three neuronal modules, the twenty genes with the most connections out of the top 150 connections in the module are illustrated. (B) For the three neuronal modules, the ten areas showing the highest expression of the module eigengene were visualized using Brain Explorer (http://www.brain-map.org). A superficial view of the brain is shown on the right, and an in-depth view is shown on the left. As some regions were available for only one of the two individuals, the regions are shown in both brains.
Figure 2 Modules correspond to specific neuronal sub-groups acting in specific regions. (A) For the three neuronal modules, the twenty genes with the most connections out of the top 150 connections in the module are illustrated. (B) For the three neuronal modules, the ten areas showing the highest expression of the module eigengene were visualized using Brain Explorer (http://www.brain-map.org). A superficial view of the brain is shown on the right, and an in-depth view is shown on the left. As some regions were available for only one of the two individuals, the regions are shown in both brains.CC BY · PubMed Central
Figure 3 Rare and common variations in ASD perturb shared neuronal modules. (A) Color map showing the different modules in the WGCNA analysis. Below it, heat maps depicting, for each module, the relative risk (RR) for harboring genes with rare mutations (top), the enrichment for low GWAS p-values in the AGRE cohort (center) and the combined enrichment for low GWAS p-values across the three GWAS (bottom). The intensity of the red hue corresponds to higher enrichment of common or rare variants. (B) For each module, the enrichment for low GWAS P-values (−log10 P) in the AGRE cohort (top) or combined across the three cohorts (bottom) is plotted against the relative risk for rare mutations. The color of the points corresponds to the names of the modules. (C) The connections in the two neuronal modules enriched for common and rare variations, Lightgreen (left) and Salmon (right), are visualized. Three highly connected genes in each module (hub genes) are shown in red; genes with a gene-wide p-value<0.05 in light blue, and genes with known rare mutations in autism in yellow.
Figure 3 Rare and common variations in ASD perturb shared neuronal modules. (A) Color map showing the different modules in the WGCNA analysis. Below it, heat maps depicting, for each module, the relative risk (RR) for harboring genes with rare mutations (top), the enrichment for low GWAS p-values in the AGRE cohort (center) and the combined enrichment for low GWAS p-values across the three GWAS (bottom). The intensity of the red hue corresponds to higher enrichment of common or rare variants. (B) For each module, the enrichment for low GWAS P-values (−log10 P) in the AGRE cohort (top) or combined across the three cohorts (bottom) is plotted against the relative risk for rare mutations. The color of the points corresponds to the names of the modules. (C) The connections in the two neuronal modules enriched for common and rare variations, Lightgreen (left) and Salmon (right), are visualized. Three highly connected genes in each module (hub genes) are shown in red; genes with a gene-wide p-value<0.05 in light blue, and genes with known rare mutations in autism in yellow.CC BY · PubMed Central
Figure 4 Contribution to ASD risk of common variation in the neuronal sub-networks. Genetic risk scores were calculated for each individual in the AGP and SSC cohorts, based on the genotypes of 79,079 tag SNPs and the association signal in these SNPs in the AGRE cohort. These scores were used to predict ASD status in a logistic regression model. To test the Lightgreen and Salmon modules, the analysis was limited to tag SNPs residing in genes in these modules. In each module and cohort, different series denote different thresholds of P-values, from PT<0.1 to PT<0.5.
Figure 4 Contribution to ASD risk of common variation in the neuronal sub-networks. Genetic risk scores were calculated for each individual in the AGP and SSC cohorts, based on the genotypes of 79,079 tag SNPs and the association signal in these SNPs in the AGRE cohort. These scores were used to predict ASD status in a logistic regression model. To test the Lightgreen and Salmon modules, the analysis was limited to tag SNPs residing in genes in these modules. In each module and cohort, different series denote different thresholds of P-values, from PT<0.1 to PT<0.5.CC BY · PubMed Central
Figure 5 Expression of neuronal modules during developmental stages. The temporal expression pattern is plotted for the modules Salmon (A), Grey60 (B) and Lightgreen (C), along with the pattern of the entire gene set (D). For each module, the average normalized expression across different brain regions for the 50 most connected genes is shown in different ages, overlaid by a smoothed signal (dashed line). pcw, post-conceptional weeks; mos, months; yrs, years.
Figure 5 Expression of neuronal modules during developmental stages. The temporal expression pattern is plotted for the modules Salmon (A), Grey60 (B) and Lightgreen (C), along with the pattern of the entire gene set (D). For each module, the average normalized expression across different brain regions for the 50 most connected genes is shown in different ages, overlaid by a smoothed signal (dashed line). pcw, post-conceptional weeks; mos, months; yrs, years.CC BY · PubMed Central

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Metadata

Authors
Ben-David, E., & Shifman, S.
Affiliations
Hebrew University of Jerusalem (IL)
Corresponding author
Shifman, Sagiv
ORCID
Shifman, Sagiv
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2012-03-08
Volume
8
Issue
3
Pages
e1002556
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1002556
PMC
PMC3297570
OpenAlex
W2129185980
Cited by
145
References
75
Citations by year
2026: 5 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 10 · 2019: 13 · 2018: 8 · 2017: 11 · 2016: 14 · 2015: 18 · 2014: 25 · 2013: 14 · 2012: 8
FWCI
10.63
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Autism Speaks
  • Legacy Heritage Fund
  • Simons Foundation Autism Research Initiative
  • Israel Science Foundation
  • University of California, Los Angeles
  • National Institute of Mental Health (U24MH081810)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
Keywords
autism spectrum disorder, gene co-expression network, neuronal genes, rare variants, common genetic variants, de novo mutations, synaptic plasticity, neuroplasticity, polygenic risk, brain gene expression
MeSH terms
Brain, Brain Mapping, Child, Child Development Disorders, Pervasive, Gene Expression Regulation, Humans, Learning, Memory, Mutation, Nerve Net, Neurons, Polymorphism, Genetic, Genetic Predisposition to Disease, Chromosome Pairing, Gene Regulatory Networks

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