Codon bias among synonymous rare variants is associated with Alzheimer’s disease imaging biomarker

Abstract

*Corresponding AuthorAlzheimer's disease (AD) is a neurodegenerative disorder with few biomarkers even though it impacts a relatively large portion of the population and is predicted to affect significantly more individuals in the future. Neuroimaging has been used in concert with genetic information to improve our understanding in relation to how AD arises and how it can be potentially diagnosed. Additionally, evidence suggests synonymous variants can have a functional impact on gene regulatory mechanisms, including those related to AD. Some synonymous codons are preferred over others leading to a codon bias. The bias can arise with respect to codons that are more or less frequently used in the genome. A bias can also result from optimal and non-optimal codons, which have stronger and weaker codon anti-codon interactions, respectively. Although association tests have been utilized before to identify genes associated with AD, it remains unclear how codon bias plays a role and if it can improve rare variant analysis. In this work, rare variants from whole-genome sequencing from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were binned into genes using BioBin. An association analysis of the genes with AD-related neuroimaging biomarker was performed using SKAT-O. While using all synonymous variants we did not identify any genomewide significant associations, using only synonymous variants that affected codon frequency we identified several genes as significantly associated with the imaging phenotype. Additionally, significant associations were found using only rare variants that contains an optimal codon in among minor alleles and a non-optimal codon in the major allele. These results suggest that codon bias may play a role in AD and that it can be used to improve detection power in rare variant association analysis.

CUBAP: an interactive web portal for analyzing codon usage biases across populations

“…For instance, traditional genetic analyses of complex diseases rarely evaluate the effects of synonymous codon usage biases because they are generally thought to not contribute significantly to disease. However, recent studies have shown that synonymous codon usage alone significantly alters protein levels and can have a causal effect on Alzheimer's disease ( 44 ), cancer ( 45 , 46 ) and multiple sclerosis ( 45 ). CUBAP enables researchers to query synonymous codon usage biases in genes identified in case-control studies to determine the extent to which codon usage biases already exist within various populations.…”

“…Additionally, a synonymous mutation in UBE1 associated with developing X-linked infantile spinal muscular atrophy significantly lowers UBE1 expression and changes exon methylation ( 43 ). Synonymous rare variants are also associated with Alzheimer's disease biomarkers ( 44 ), and shifts in codon usage biases alone can yield high diagnostic accuracy in a variety of other diseases including cancers and multiple sclerosis ( 45 ). Furthermore, codon usage biases in rat oncogenes directly regulate tumor growth ( 46 ).…”

Effects of rrm1 on NNV Resistance Revealed by RNA-seq and Gene Editing

“…Four SNPs in the exon were synonymous codons. In another study on Alzheimer's disease, several genes related to the disease were associated with synonymous variants (Miller et al 2018). Therefore, these studies suggest that synonymous codons are worth studying for the detection and prevention of disease.…”

Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report

“…Nucleotide sequence changes in coding regions are primarily assessed using protein-level conservation analysis that assesses their effect on protein sequence (see below). However, nucleotide-level conservation analysis may be considered useful for investigating effect of sequence changes on the fitness of splicing regulatory motifs, or mRNA secondary structure and stability, translation efficiency [22][23][24], or to infer functional importance of non-coding sequences (introns, untranslated regions and other extragenic sequence). Indeed, it is a factor denoted for review of synonymous variants (code BP7) in the ACMG/AMP guidelines [5].…”