C002 HTT repeat allele structures as cis-acting modifiers of Huntington disease age at onset

<h3>Background</h3> Huntington disease (HD) is caused by a CAG expansion within a complex glutamine encoding CAG/CAA and proline encoding CCA/CCG/CCT repeat in HTT with typical structure (CAG)x(CAACAG)1(CCGCCA)1(CCG)y(CTT)2. Atypical synonymous variants within the HTT repeat have been associated with variation in age at onset (AAO). <h3>Aim</h3> To determine whether the AAO modifier effects associated with the atypical repeat structures are directly attributable to the structures or mediated by other HTT variants in linkage disequilibrium with these structures. <h3>Methods</h3> Tagging SNPs for the HTT atypical structures were identified from previous clinical phenotype GWAS, or by conducting structure-specific GWAS with the data from the HD Genetic Modifiers GWA6 cohort. The associations between AAO and/or the atypical structures and/or nearby tagging SNPs were determined by regression analysis. <h3>Results</h3> Atypical alleles with the (CAG)x(CAACAG)2(CCGCCA)1(CCG)7(CTT)3 structure were very strongly associated with tagging SNPs, and we could not distinguish the protective effects on AAO between the tagging SNPs and the repeat structure. Although atypical alleles with the (CAG)x(CCG)11-13(CTT)2 structure were also strongly associated with tagging SNPs, regression analyses indicated the primary effect on accelerating AAO was most likely attributable to the structure. Atypical alleles with (CAG)x(CCG)8-10(CTT)2, (CAG)x(CCGCCA)1(CCG)7-10(CTT)2, and (CAG)x(CAACAG)1(CCG)6-12(CTT)2 structures were not strongly tagged with any SNPs and were associated with multiple HTT haplotypes. <h3>Conclusion</h3> These data strongly support the hypothesis that atypical HTT repeat allele structures are the primary causal variants for the modifier associations with AAO, rather than nearby flanking variants.