Journal: Nature neuroscience
Article Title: Molecular and network-level mechanisms explaining individual differences in autism spectrum disorder
doi: 10.1038/s41593-023-01259-x
Figure Lengend Snippet: a, Schematic of transcriptomics analysis to test whether gene expression explains atypical connectivity in each subgroup. First, we calculated gene expression at each brain region (ROI) and atypical connectivity (RSFC) summed over ROIs for each subgroup. Second, we performed PLS regression for each subgroup and estimated the significance of each PLS model using a spatial permutation (‘spin’) test27,56. The PLS models for all four subgroups were significant (subgroup 1: P = 0.014; subgroup 2: P < 0.001; subgroup 3: P < 0.001; subgroup 4: P < 0.001; all statistics in Supplementary Table 3). Third, we ranked genes by PLS gene weights in each model. b, Heat map of similarity between subgroup gene rank lists (average of RBO for top 1,000 positively ranked genes and RBO for the top 1,000 negatively ranked genes between subgroups). Each subgroup was associated with a distinct set of genes (RBO = 0.36–0.59, 1 is perfect similarity). c–e, Heat maps of gene set enrichment for each subgroup’s ranked gene weights for ASD-related gene sets (c), nonpsychiatric disease-related gene sets (d), psychiatric disorder-related gene sets (e), synaptic signaling gene sets (f), immune signaling gene sets (g) and protein translation gene sets (h). Full GSEA results are in Supplementary Table 4. All subgroups were enriched for ASD-related gene sets, but not for unrelated diseases. Color indicates strength of negative log-transformed FDR for normalized enrichment score multiplied by the sign of the gene weight (+1 or −1). ADHD, attention-deficit/hyperactivity disorder; CNS, central nervous system; GAD, generalized anxiety disorder; GPCR, G-protein-coupled receptor; ID, intellectual disability; MDD, Major depressive disorder; MSA, multiple system atrophy; PD, personality disorder; RDNV, rare de novo variants.
Article Snippet: To investigate whether brain-wide gene expression from the AHBA atlas predicts ASD-related changes in functional connectivity, we utilized PLS using the SIMPLS algorithm (MATLAB plsregress) with the 230 brain regions as samples, the predictors ( X ) as the 10,438 gene expression values across these samples, and one response variables ( y ): the net atypical connectivity (sum of positive atypical connectivity to each ROI minus the absolute value of the sum of negative atypical connectivity to each ROI).
Techniques: Gene Expression, Transformation Assay
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![To further assess relationships between gene expression with atypical connectivity and behavior in larger useable samples (that is, now including subjects with usable fMRI data who were excluded from primary analyses due to incomplete behavioral assessments) we started with the N = 782 subjects with usable scan data, and split the NVIQ = 590 subjects with VIQ into VIQ bins (ASD subjects with [NVIQ>120 = 127] VIQ > = 120, [N85≤VIQ≤120 = 383] VIQ 85–120, or [NVIQ<85 = 80] VIQ < = 85). We also split the NADOS-2 = 353 subjects with ADOS-2 assessment into bins by calculating social affect divided by RRB. The social affect > RRB bin (social affect / RRB > 1) had NSA>RRB = 113 ASD subjects and the RRB > social affect bin (social affect / RRB >1) had NSA<RRB = 171 ASD subjects; the NSA=RRB = 69 ASD subjects with SA/RRB = 1 were not included in either ADOS-2 bin. The overlap of subjects between the NVIQ = 590 subjects with VIQ and NADOS-2 = 353 subjects with ADOS-2 was the NVIQ;ADOS-2 = 299 ASD subjects in the main analysis. We used the same PLS and gene set enrichment procedure as in Fig. 5 (see b,d,f,h,j,l in box) to assess the relationship of these binned subjects’ atypical connectivity with gene expression. Heatmaps of gene set enrichment for each subgroup’s ranked gene weights for (a-b) ASD-related gene sets, (c-d) nonpsychiatric disease-related gene sets, (e-f) psychiatric disorder-related gene sets, (g-h) synaptic signaling gene sets, (i-j) immune signaling gene sets, and (k-l) protein translation gene sets. Color indicates strength of negative log transformed FDR for normalized enrichment score multiplied by sign of gene weight (+1 or −1). The results were consistent with our predictions: gene set enrichments for the low-VIQ bin resembled those for subgroup 2 (featured low Verbal IQ) and enrichments for the high-VIQ bin resembled those for subgroup 1 (featured above-average VIQ). See further description of results in Supplementary Discussion. The P values were calculated and FDR-corrected as in Fig. 5.](https://pub-med-central-images-cdn.bioz.com/pub_med_central_ids_ending_with_6249/pmc11446249/pmc11446249__nihms-1959912-f0015.jpg)