A Role for Non-coding Genetic Variants in Polyglutamine Diseases

Abstract

Polyglutamine diseases are progressive monogenic neurodegenerative diseases which are caused by an expanded trinucleotide repeat (CAG) in the coding region of the relevant disease-causing gene. There are nine polyglutamine diseases: spinocerebellar ataxia 1, spinocerebellar ataxia 2, spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, spinocerebellar ataxia17, dentatorubropallidoluysian atrophy (DRPLA), spinal bulbar muscular atrophy and Huntington’s disease (HD). Genome-wide association studies (GWAS) have identified genetic variants (single nucleotide polymorphisms [SNPs]), mostly located in the non-coding region of the genome, which associate with the age of onset and progression of Huntington’s disease. To identify the genetic variants that regulate the expression of genes associated with HD and DRPLA disease pathology, we used CoDeS3D to identify tissue specific regulatory connections which modify the expression of HTT (HD causing gene) and ATN1 (DRPLA causing gene) across 13 brain tissues. Similarly, we used CoDeS3D to identify tissue specific regulatory connections in the intronic regions adjacent to the CAG repeat containing exons with polyglutamine disease causing genes and other genes across 13 brain tissues. We found that genetic variants located in the disease-causing genes (specifically, those nearby to the CAG repeat exon) impact on pathways relevant to polyglutatmine disease pathology, such as disease progression, resulting in a disruption of healthy gene regulation. Overall, we identified putative trans regulation of genes associated with polyglutamine disease pathology: neurodegeneration, autophagy, DNA repair, neurodevelopment, dementia, apoptosis, and nucleocytoplasmic transport. We propose that these regulatory changes could explain why these the nine CAG repeat regions we investigated are associated with similar pathologies yet have such different comorbidities.