Abstract
We previously proposed that changes in the efficiency of protein translation are associated with autism spectrum disorders (ASDs). This hypothesis connects environmental factors and genetic factors because each can alter translation efficiency. For genetic factors, we previously tested our hypothesis using a small set of ASD-associated genes, a small set of ASD-associated variants, and a statistic to quantify by how much a single nucleotide variant (SNV) in a protein coding region changes translation speed. In this study, we confirm and extend our hypothesis using a published set of 1,800 autism quartets (parents, one affected child and one unaffected child) and genome-wide variants. Then, we extend the test statistic to combine translation efficiency with other possibly relevant variables: ribosome profiling data, presence/absence of CpG dinucleotides, and phylogenetic conservation. The inclusion of ribosome profiling abundances strengthens our results for male–male sibling pairs. The inclusion of CpG information strengthens our results for female–female pairs, giving an insight into the significant gender differences in autism incidence. By combining the single-variant test statistic for all variants in a gene, we obtain a single gene score to evaluate how well a gene distinguishes between affected and unaffected siblings. Using statistical methods, we compute gene sets that have some power to distinguish between affected and unaffected siblings by translation efficiency of gene variants. Pathway and enrichment analysis of those gene sets suggest the importance of Wnt signaling pathways, some other pathways related to cancer, ATP binding, and ATP-ase pathways in the etiology of ASDs.
Highlights
Autism spectrum disorders (ASDs) are characterized by difficulties in social interaction, difficulties in communication, and repetitive behaviors (Geschwind and State 2015)
We checked our hypothesis that the codon usage shift of rare and moderately common single nucleotide variant (SNV) is associated with autism (Poliakov et al 2014) in the simplest way
We find that affected individuals have a significantly higher proportion of SNVs with a positive shift score
Summary
Autism spectrum disorders (ASDs) are characterized by difficulties in social interaction, difficulties in communication, and repetitive behaviors (Geschwind and State 2015). Due to the increase in prevalence, research efforts to identify factors contributing to ASD have intensified These efforts include the collection and sequencing of DNA samples from hundreds of families (Krumm et al 2015). Other environmental studies have considered the role of prenatal and perinatal factors These are of interest since genetic studies have identified an enrichment for mutations in genes that play a role in fetal brain development (Sanders et al 2015; de la Torre-Ubieta et al 2016; Yuen et al 2017). The hypothesis that protein translation is affected in ASD is reviewed in (de la Torre-Ubieta et al 2016) We analyze variants according to ribosome profiling occupancy, evolutionary conservation, and CpG context to evaluate whether single nucleotide variants (SNVs) present in affected individuals and absent in siblings (or vice versa) differ statistically by any of these characteristics pertinent to gene translation
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