Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism

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.

Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat

“…Blood repeat length inversely correlated with AAO and explained ~ 45% of the AAO variability ( P = 7.7 ℮ -36; Fig. 1 a, red dots), consisted with previous studies [ 4 , 25 , 36 ]. A similar correlation was observed between brain repeat length and AAO, with repeat length explaining ~ 55% of the AAO variability ( P = 4.7 ℮ -08; Fig.…”

“…Our analyses of repeat instability in different brain tissues do not immediately point to any clear correlation with brain regions implicated either through neuropathological or neuroimaging studies to be susceptible in XDP [ 10 – 15 , 36 ]. e.g .…”

“…Given the inverse correlation of CCCTCT repeat length with AAO these observations implicate somatic expansion as a driver of the rate of onset of XDP. Notably, a GWAS identified two genes, MSH3 and PMS2 as modifiers of the age of onset of XDP [ 36 ]. These genes are also modifiers of HD age at onset [ 30 ] and encode DNA mismatch repair proteins that modulate the somatic instability of disease-associated trinucleotide repeats, including the HTT CAG repeat [ 30 , 37 – 39 ].…”

“…Studies of other repeat expansion diseases indicate that somatic expansion is a likely common mechanism driving pathogenesis [ 27 , 32 – 35 ]. Significantly, a recent genome-wide association study (GWAS) for modifiers of XDP [ 36 ] identified genes ( MSH3, PMS2 ) with known roles in in repeat instability [ 30 , 37 – 39 ] that also modify HD [ 30 , 40 ], indicating that a common mechanism at the level of repeat instability extends to XDP. The XDP CCCTCT repeat exhibits intergenerational instability, with repeat length tending to increase in transmissions from mothers and to decrease in transmissions from fathers [ 4 , 25 ].…”

The Genetic Landscape of Parkinsonism-Related Dystonias and Atypical Parkinsonism-Related Syndromes

“…The length of a polymorphic ( CCCTCT ) n repeat within the SVA retrotransposon insertion was shown to inversely correlate with age at onset (AAO) and TAF1 expression, and to positively correlate with disease severity and cognitive dysfunction [ 36 , 37 ]. Three additional genetic modifiers of AAO for XDP—rs245013 and rs33003 in MSH3 and rs62456190 adjacent to the ANKRD61, EIF2AK1 and PMS2 genes—have been described [ 38 ]. Together with the hexanucleotide repeat, these signals account for nearly two thirds of the AAO variability in XDP.…”