Abstract
X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10−8). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington’s disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.
Highlights
X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability
We showed that the length of a polymorphic (CCCTCT)n repeat within this SVA retrotransposon insertion correlates inversely with age at onset (AAO)[4,5] and TAF1 expression, as well as positively with disease severity and cognitive dysfunction[4]
Repeat numbers showed an inverse correlation with AAO (Pearson product-moment correlation: r = −0.703, p < 2.2 × 10−16), explaining 49.3% of the AAO difference in our 353 XDP patients (R2 = 0.493)
Summary
X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington’s disease, likely through a common pathway influencing repeat instability. Our findings (i) confirm that genome-wide significant genetic modifiers can be identified in small but homogeneous samples of patients with monogenic disease; (ii) reveal a biologically plausible mechanism of disease modification in XDP; and (iii) pathophysiologically link XDP to Huntington’s disease (HD, OMIM #143100), another repeat expansion disorder with severe striatal neurodegeneration as an overlapping feature of both diseases
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