Comprehensive literature data-mining analysis reveals a broad genetic network functionally associated with autism spectrum disorder

Abstract

Previous studies have indicated that genetic factors are the predominate cause of Autism spectrum disorder (ASD). Nevertheless, to the best of our knowledge, to date no systematic study has summarized these data and provided an objective, complete list of genes with demonstrated associations with ASD. The present study included a literature data mining analysis of >2,064 articles including publications from January 2000 to April 2016, which identified 488 ASD target genes. Gene set enrichment analysis (GSEA), sub‑network enrichment analysis (SNEA) and network connectivity analysis (NCA) were conducted to assess the functional profile and pathogenic significance of these genes. A total of 2 literature metrics were proposed to prioritize the curated ASD genes with specific significance. This approach resulted in the development of an ASD genetic database. Subsequent analysis indicated that 391 of the 488 genes were enriched in 97 biological pathways (P<1x10‑8), demonstrating significant functional associations with each other. The majority of these curated ASD genes also serve significant roles in the pathogenesis of other neuropsychiatric disorders. These results suggest that the genetic causes of ASD are within a large network composed of functionally‑associated genes. The genetic database, together with the metric scores developed in the present study, provides a basis for future biological/genetic modeling in the field.

Figure 1

Distribution of 488 genes among different association types. The X-axis represents the gene index (gene 1-488). The Y-axis represents the types of gene-ASD associations. The color at a coordinate (x, y) represents the number of articles reporting a 'y' association type for the gene 'x'. The legend on the right denotes the number-color correspondence; the continuous change of color from blue to red represents a change of number from 0 to 10, where 0 signifies that there are no articles supporting the association. ASD, autism spectrum disorder.

Figure 2

Histogram of the publications describing gene-disease associations between 488 unique genes and autism spectrum disorder. (A) Histogram of article publication date. (B) Histogram of the number of novel genes identified in each year.

Figure 3

All autism spectrum disorder-gene single reference associations rank-ordered by QScore. A higher QScore for a given association was derived from a combination of a recent publication date (blue bar) and high citation rate (red bar). QScore, quality score.

Figure 4

Pathways for (A) behavior, (B) neural function and (C) brain function/development. In all networks, the weight of the line (number attached to the line) between two nodes is the number of genes shared by those two pathways. The size of the nodes represents the P-value (−log₁₀ transformed) of the enriched pathway. The brighter the color of a node, the higher the number of the pathways connected to the node.

Figure 5

Disease-disease interaction network between autism spectrum disorder and the top 10 mental disorders from the sub-network enrichment analysis. CNTNAP2, contactin associated protein like 2; SLC6A4, solute carrier family 6 member 4; MECP2, methyl CpG-binding protein 2; OXT, oxytocin neurophysin 1 prepropeptide; IL6, interleukin 6; FMR1, fragile × mental retardation 1.

Figure 6

Gene network of top 14 genes by NScore and QScore. (A) QScore group; the brighter the color (red), the higher the QScore. (B) NScore group; the brighter the color (green), the higher the NScore. The size of each node represents the number of pathways (from the pathway enrichment analysis) a gene was identified in. The weight of the line between any two nodes is the number of pathways shared by those two genes. NScore, novelty score; QScore, quality score. Due to high number of edges, the weights on the edge may not differentiable. Please refer to ASD_GD→Related Genes, where the related pathways of each gene have been provided.