Over 30 diseases are caused by expansion of microsatellite sequences; nine by expanded CAG tracts encoding polyglutamines. These include Huntington's disease (HD), several spinocerebellar ataxias (SCAs), and spinal and bulbar muscular atrophy. Longer CAG repeats are associated with earlier age-at-onset (AAO), but studies suggest additional modifying factors. DNA repair pathways were recently associated with HD motor AAO in a GWAS. We aimed to investigate whether the modifying effects of DNA repair gene variants can be extended to other polyglutamine diseases.
We collected an independent cohort of 1462 subjects with HD and polyglutamine SCAs, and genotyped SNPs selected from the most significant hits in the HD study.
In an overall analysis of DNA repair pathways, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs, p=1.43×10−5). Significant associations were also found for HD (p=0.00194), all SCAs (p=0.00107), SCA2 (p=0.0035), SCA6 (p=0.00162). Two SNPs showed individual significant associations. All associations follow the same direction as the HD GWAS.
We show DNA repair genes modify AAO not only in HD, but also in polyglutamine SCAs. This suggests a common pathogenic mechanism for these diseases. Manipulation of DNA repair pathways may offer therapeutic opportunities in multiple diseases.