Table 1.
Overview of five datasets and the independent scoring systems used to shortlist ASD genes for overlapping analysis.
Fig 1.
Flowchart of the analysis for the paper: Arrow indicates the steps of each analysis.
Fig 2.
Shortlisting of common ASD factors.
(A) JVenn Diagram of all overlapping genes from the scoring systems used. Underlined numbers indicate sets overlapped with SFARI. (B) Size of each set of shortlisted genes. (C) The number of genes that are shared by or specific to the lists.
Fig 3.
Heatmap of 292 genes after filtering for low expressed genes (TPM<3).
The tissues were indicated on the top. Scale bar on top right corner showed the scale of mRNA expression for each gene: grey is TPM = 0, green is 0–3, yellow is 9–31, orange is 31–99, red is > 99. (A) The 91 genes in the CNS geneset have an average median of TMP<3 in the peripheral tissues. (B) The 201 CNS+PT genes were expressed both CNS and peripheral tissues with TMP>3.
Fig 4.
Protein expression of CNS geneset from HPA across tissues.
Genes are displayed in order of decreasing protein expression.
Fig 5.
Protein expression of CNS+PT geneset from HPA across tissues.
Genes are displayed in order of decreasing expression.
Table 2.
Interacting ASD genes in tissue-specific networks.
Genes in bold denote ASD genes (POGZ and ANKRD11) present in nearly all networks.
Fig 6.
(A) Selected genes from 91 CNS geneset, highlighting that Nervous development (blue), Trans-synapses (red) and Ion transmembrane transportation (yellow) are the most enriched pathways. (B) Selected genes highlighted from the 200 CNS+PT geneset, demonstrating that the Nervous development (blue), the Chromatin organisation (green) and Gene regulation (red) were the among the most significant pathways. (C) Glutamatergic/GABAergic synapses, (D) Cell signalling and Hormonal secretion pathways from the combined 291 genes all linked to calcium signalling, suggesting that Calcium signalling is the most interconnected pathways linking the ASD signalling pathways. Edges represent combined gene score, node colours represent selected GO terms (A-B) and KEGG pathways (C,D) The colours for 3D correspond to the following; Yellow-Calcium Signalling, Green -MAPK Signalling, Red -cAMP signalling, Blue—Wnt Signalling, Brown—thyroid signalling, purple–Insulin Signalling, Orange–Aldosterone Synthesis and Secretion.
Table 3.
Key Go terms of the CNS-specific and ubiquitous ASD genesets.
Fig 7.
Co-Morbid phenotypes associated with ASD.
(A) Top 50 terms enriched in CNS geneset, (B) top 50 terms enriched in CNS+PT geneset. X-axis denotes ratio of enrichment. Dark blue are terms below FDR < 0.05.
Table 4.
Genes dysregulated in ASD expression studies that overlapped with our geneset.
Fig 8.
Sex-biased expression of the ASD genesets.
Biased expression of the ASD genesets in female (A) and male (B) brain regions. Values are expressed as FDR in red and Log2 odds ratio in green with gradients. N.S for not significant. (C) Overlap of 34 ASD genes with sex-biased splicing genes. (D) Bullseye plot showing enrichment of ASD geneset in brain regions with most significant correlation in cerebral cortex throughout brain development. A1C -primary auditory cortex, AMY—amygdaloid complex, CBC—cerebellar cortex, DFC -dorsolateral prefrontal cortex, HIP—hippocampus, IPC—posterior inferior parietal cortex, ITC—inferolateral temporal cortex, M1C-primary motor cortex, MD—mediodorsal nucleus of thalamus, MFC—medial prefrontal cortex, OFC -orbital frontal cortex, S1C - primary somatosensory cortex, STC—posterior(caudal) superior temporal cortex, STR -striatum, VFC—ventrolateral prefrontal cortex, and V1C - primary visual cortex.
Fig 9.
Overlap of ASD genes with other conditions.
A) Comparison of the ASD geneset with Pyschgenet (SCZ, BP, MDD) defines a network of 94 overlapping genes (green) and 198 ASD-unique genes (blue). B) matrix of overlaps between ASD/Psychiatric (SCZ, BP, MDD) and peripheral (IBD, ARY. T1D and T2D) conditions. C) Network of ASD genes and overlaps with peripheral (IBD, ARY. T1D and T2D) conditions, with orange circle for non-overlapping genes. IBD—Inflammatory bowel disease, Ary—Arrythmia, T1D - type 1 diabetes, T2D - type 2 diabetes. SCZ–schizophrenia, BP–bipolar disorder, MDD–major depressive disorder.
Table 5.
Converging ASD candidate genes on E/I balance and calcium signalling pathway.
Fig 10.
From fertilization to full development, mutations in chromatin modelling and transcription factors can contribute to altered developmental trajectory in brain formation, synaptogenesis, and organogenesis. Alterations in synaptic and ion channel genes may lead to perturbed action potentials and imbalance of E/I synapses that can contribute to the core ASD symptoms and CNS comorbidity such as epilepsy and motor functions. However, alterations in cellular, hormonal signalling and gene regulation can contribute to peripheral co-morbidities such as altered facial phenotypes and behaviour. Calcium signalling appears acting as a hub among the CNS and peripheral pathways.