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. 2021 May 16;22(10):5248.
doi: 10.3390/ijms22105248.

Do Autism Spectrum and Autoimmune Disorders Share Predisposition Gene Signature Due to mTOR Signaling Pathway Controlling Expression?

Ekaterina A Trifonova  1 , Alexandra I Klimenko  1 , Zakhar S Mustafin  1 , Sergey A Lashin  1   2 , Alex V Kochetov  1   2
Affiliations

Do Autism Spectrum and Autoimmune Disorders Share Predisposition Gene Signature Due to mTOR Signaling Pathway Controlling Expression?

Ekaterina A Trifonova et al. Int J Mol Sci. .

Abstract

Autism spectrum disorder (ASD) is characterized by uncommon genetic heterogeneity and a high heritability concurrently. Most autoimmune disorders (AID), similarly to ASD, are characterized by impressive genetic heterogeneity and heritability. We conducted gene-set analyses and revealed that 584 out of 992 genes (59%) included in a new release of the SFARI Gene database and 439 out of 871 AID-associated genes (50%) could be attributed to one of four groups: 1. FMRP (fragile X mental retardation protein) target genes, 2. mTOR signaling network genes, 3. mTOR-modulated genes, and 4. vitamin D3-sensitive genes. With the exception of FMRP targets, which are obviously associated with the direct involvement of local translation disturbance in the pathological mechanisms of ASD, the remaining categories are represented among AID genes in a very similar percentage as among ASD predisposition genes. Thus, mTOR signaling pathway genes make up 4% of ASD and 3% of AID genes, mTOR-modulated genes-31% of both ASD and AID genes, and vitamin D-sensitive genes-20% of ASD and 23% of AID genes. The network analysis revealed 3124 interactions between 528 out of 729 AID genes for the 0.7 cutoff, so the great majority (up to 67%) of AID genes are related to the mTOR signaling pathway directly or indirectly. Our present research and available published data allow us to hypothesize that both a certain part of ASD and AID comprise a connected set of disorders sharing a common aberrant pathway (mTOR signaling) rather than a vast set of different disorders. Furthermore, an immune subtype of the autism spectrum might be a specific type of autoimmune disorder with an early manifestation of a unique set of predominantly behavioral symptoms.

Keywords: FMRP; SFARI Gene database; autism spectrum disorder (ASD); autoimmune disorders (AID); bioinformatics; mTOR; vitamin D3.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Venn diagram representing the relationship of the four categories related to the mTOR signaling and vitamin D-sensitive genes. All sets of genes were preliminarily intersected with high-scored candidates from the SFARI Gene database.
Figure 2
Figure 2
Venn diagram representing the relationship of the four categories related to the mTOR signaling and vitamin D-sensitive genes. All sets of genes were preliminarily intersected with whole AID gene set.
Figure 3
Figure 3
Venn diagram representing the complete intersection of ASD and AID genes of the four categories related to the mTOR signaling and vitamin D-sensitive genes.
Figure 4
Figure 4
mTOR signaling and mTOR-modulated AID genes interacting with non-categorized AID genes. The right legend shows the color of the node description. The left legend shows the interaction type colors. The complete list of the most connected genes and their nodes degree is given in Supplementary Table S3.
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