Abstract
ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990
Highlights
Interpretation: We show that DNA repair genes significantly modify age at onset in Huntington’s disease (HD) and spinocerebellar ataxia (SCA), suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models
Our data implicate a common mechanism by which genetic variation in DNA repair pathways underlies age at onset of disease in multiple polyglutamine diseases
Rare loss-of-function variants in DNA repair genes cause multiple recessive ataxias[22]; ATM encodes a master regulator of DNA repair following double-strand breaks,[23] PNPK encodes a DNA-specific kinase that facilitates DNA repair,[24] APTX encodes a protein that interacts with PARP1 to mediate single strand DNA breaks,[25] and mutations in TDP1 give defects in single-strand break repair.[26]
Summary
The polyglutamine diseases, including Huntington’s disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. Interpretation: We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models This offers novel therapeutic opportunities in multiple diseases. Longer CAG repeat tracts lead to earlier age at onset (AAO), though the relationship varies between diseases (see Table 1).[3,4] Not all of the difference in AAO is accounted for by CAG repeat length, and in Huntington’s disease (HD)[4] and at least spinocerebellar ataxia (SCA) types 2 and 3,5 a substantial portion of this residual variance is heritable, suggesting the existence of additional modifying factors within the genome. We demonstrate significant associations between variants in genes involved in DNA repair pathways and the AAO of polyglutamine diseases as a group as well as with some polyglutamine diseases individually
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