Personalized Perturbation Profiles Reveal Concordance between Autism Blood Transcriptome Datasets

Abstract

The complex heterogeneity of Autism Spectrum Disorder (ASD) has made quantifying disease specific molecular changes a challenge. Blood based transcriptomic assays have been performed to isolate these molecular changes and provide biomarkers to aid in ASD diagnoses, etiological understanding, and potential treatment1–6. However, establishing concordance amongst these studies is made difficult in part by the variation in methods used to call putative biomarkers. Here we use personal perturbation profiles to establish concordance amongst these datasets and reveal a pool of 1,189 commonly perturbed genes and new insights into poorly characterized genes that are perturbed in ASD subjects. We find the resultant perturbed gene pools to include the following unnamed genes: C18orf25, C15orf39, C1orf109, C1orf43, C19orf12, C6orf106, C3orf58, C19orf53, C17orf80, C4orf33, C21orf2, C10orf2, C1orf162, C10orf25 and C10orf90. Investigation into these genes using differential correlation analysis and the text mining tool Chilibot reveal interesting connections to DNA damage, ubiquitination, R-loops, autophagy, and mitochondrial damage. Our results support evidence that these cellular events are relevant to ASD molecular mechanisms. The personalized perturbation profile analysis scheme, as described in this work, offers a promising way to establish concordance between seemingly discordant expression datasets and expose the relevance of new genes in disease.

Uncharacterized protein c17orf80: a novel interactor of human mitochondrial nucleoids

“…To date, there is no information regarding the molecular function(s) of c17orf80, and clinically significant data are very limited. However, some genetic association studies linked c17orf80 to autism spectrum disorder (Laird and Maertens, 2021; Mencer et al, 2021; Shaath, 2013) as well as pancreatic (Makler and Narayanan, 2017) and prostate cancers (Cheng et al, 2018). Many orphan proteins detected in genetic screens remain uncharacterized, as their molecular functions have not yet been investigated and are generally difficult to predict (Kustatscher et al, 2022).…”