RESUMEN
Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning tools in Python, demonstrated superior performance among submissions. Furthermore, the study observed that state-of-the-art deep learning methods provided small but statistically significant improvement in predictive performance compared to less elaborate techniques. These findings underscore the utility of variant effect prediction, and the potential for models trained with modest resources to accurately classify VUS in genetic and clinical research.
RESUMEN
The collection of expression quantitative trait loci (eQTLs) is an important resource to study complex traits through understanding where and how transcriptional regulations are controlled by genetic variations in the non-coding regions of the genome. Previous studies have focused on associating eQTLs with traits to identify the roles of trait-related eQTLs and their corresponding target genes involved in trait determination. Since most genes function as a part of pathways in a systematic manner, it is crucial to explore the pathways' involvements in complex traits to test potentially novel hypotheses and to reveal underlying mechanisms of disease pathogenesis. In this study, we expanded and applied loci2path software to perform large-scale eQTLs enrichment [i.e., eQTLs' target genes (eGenes) enrichment] analysis at pathway level to identify the tissue-specific enriched pathways within trait-related genomic intervals. By utilizing 13,791,909 eQTLs cataloged in the Genotype-Tissue Expression (GTEx) V8 data for 49 tissue types, 2,893 pathway sets reported from MSigDB, and query regions derived from the Phenotype-Genotype Integrator (PheGenI) catalog, we identified intriguing biological pathways that are likely to be involved in ten traits [Alzheimer's disease (AD), body mass index, Parkinson's disease (PD), schizophrenia, amyotrophic lateral sclerosis, non-small cell lung cancer (NSCLC), stroke, blood pressure, autism spectrum disorder, and myocardial infarction]. Furthermore, we extracted the most significant pathways for AD, such as BioCarta D4-GDI pathway and WikiPathways sulfation biotransformation reaction and viral acute myocarditis pathways, to study specific genes within pathways. Our data presented new hypotheses in AD pathogenesis supported by previous studies, like the increased level of caspase-3 in the amygdala that cleaves GDP dissociation inhibitor and binds to beta-amyloid, leading to increased apoptosis and neuronal loss. Our findings also revealed potential pathogenesis mechanisms for PD, schizophrenia, NSCLC, blood pressure, autism spectrum disorder, and myocardial infarction, which were consistent with past studies. Our results indicated that loci2path's eQTLs enrichment test was valuable in unveiling novel biological mechanisms of complex traits. The discovered mechanisms of disease pathogenesis and traits require further in-depth analysis and experimental validation.