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. 2015 Feb;18(2):191-8.
doi: 10.1038/nn.3907. Epub 2014 Dec 22.

Genotype to phenotype relationships in autism spectrum disorders

Affiliations

Genotype to phenotype relationships in autism spectrum disorders

Jonathan Chang et al. Nat Neurosci. 2015 Feb.

Abstract

Autism spectrum disorders (ASDs) are characterized by phenotypic and genetic heterogeneity. Our analysis of functional networks perturbed in ASD suggests that both truncating and nontruncating de novo mutations contribute to autism, with a bias against truncating mutations in early embryonic development. We find that functional mutations are preferentially observed in genes likely to be haploinsufficient. Multiple cell types and brain areas are affected, but the impact of ASD mutations appears to be strongest in cortical interneurons, pyramidal neurons and the medium spiny neurons of the striatum, implicating cortical and corticostriatal brain circuits. In females, truncating ASD mutations on average affect genes with 50-100% higher brain expression than in males. Our results also suggest that truncating de novo mutations play a smaller role in the etiology of high-functioning ASD cases. Overall, we find that stronger functional insults usually lead to more severe intellectual, social and behavioral ASD phenotypes.

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Figures

Figure 1
Figure 1
The network implicated by NETBAG+ based on ASD-associated de novo SNVs and CNVs from recent studies (network is comprised of 159 genes; P = 0.036). Node sizes are proportional to the contributions of each gene to the overall network score, and edge widths are proportional to the likelihood that the corresponding gene pair contributes to the same genetic phenotype (see Methods). For clarity, only the two strongest edges for each gene are shown. Node shapes indicate types of the corresponding mutations: circles represent genes from SNVs, squares represent genes from CNVs, and diamonds represent genes affected by both mutation types. The network was divided into cohesive functional clusters (indicated by node colors) using hierarchical clustering; general functions of these clusters determined using DAVID are shown in the figure (see Supplementary Table S3 for a complete list of GO terms associated with each cluster). Grey nodes represent genes that are not members of the network clusters.
Figure 2
Figure 2
Temporal gene expression profiles in the human brain across developmental stages for implicated gene sets. Expression data were obtained from the HBT database; average expression levels at each developmental stage were calculated using all genes in a given set and error bars represent SEM. Vertical dashed lines indicate birth. (a) Expression profiles for truncating SNV genes in the network (orange), all network genes (red), network genes from CNVs (green), all truncating SNV genes (blue), and non-network SNV genes (purple). (b) Expression profiles for network genes with truncating (cyan) and non-truncating (red) mutations observed in probands. (c) Expression profiles for functional clusters (Fig. 1) of the implicated network: postsynaptic density genes (cyan), chromatin modification/regulation genes (red), signaling/cytoskeleton genes (green), and channel activity genes (blue). (d) Expression profiles for network and truncating female/male SNV genes: female truncating SNV genes (red), female network genes (green), male network genes (blue), and male truncating SNV genes (purple). Human expression data were obtained from the HBT database. Vertical dashed lines separate prenatal and postnatal developmental stages. Error bars represent SEM.
Figure 3
Figure 3
Cell type expression biases for network mutations and recurrent truncating mutations. Probands versus unaffected siblings expression biases were computed across 25 cell types of the central nervous system for implicated network genes (shown in red) and for 11 genes with recurrent truncating SNVs (blue). The biases were calculated using Mus. musculus expression data from the study by Doyle et al. To quantify the expression biases, we calculated for each cell type the difference between the average log2 expression of mouse orthologs for implicated human genes and the average log2 expression of mouse ortholog for human genes with de novo SNVs in unaffected siblings. Cell types in the figure are ordered by the magnitude of the cell type expression bias for network genes (red). The significance of the expression biases was evaluated using the Wilcoxon rank-sum one-tail test and corrected for multiple hypothesis testing using the Benjamini-Hochberg procedure with FDR=10%; significant cell types are shown in dark red/blue, and non-significant in light red/blue. P-values obtained from the two independent approaches — one based on network genes (red) and the other based on genes affected by recurrent truncating mutations (blue) — were combined using Fisher’s and Stouffer’s meta-analysis methods. The combined P-values were corrected using the Bonferroni method, and the cell types passing the significance cutoff for both meta-analyses are shown in bold. All P-values associated with the figure are presented in Supplementary Table S8.
Figure 4
Figure 4
Average numbers of de novo mutations per individual for probands with different IQs. (a) The average number of truncating SNVs (blue) and CNVs (green) per individual. (b) The average number of non-truncating SNVs (purple) and synonymous SNVs (orange) per individual. Horizontal dashed lines represent the corresponding average numbers of mutations per individual for all unaffected siblings. Error bars represent SEM.
Figure 5
Figure 5
Temporal gene expression profiles in the human brain across developmental stages for genes affected in subsets of probands with different phenotypic scores. Expression data were obtained from the HBT database; average expression levels at each developmental stage were calculated using all genes in a given set and error bars represent SEM. In each figure, probands were divided into two groups (high and low) relative to the corresponding median phenotypic scores. Expression profiles for network genes are displayed as solid lines and profiles for truncating SNVs as dashed lines. Profiles for genes affected in probands with more severe phenotypes are shown in red and less severe phenotypes in blue. Vertical dashed lines indicate birth. (a) Profiles for probands with high/low IQ. (b) Profiles for probands with low/high ADIR-S scores. (c) Profiles for probands with low/high ADIR-R scores.

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