Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington’s Disease

Abstract

Background: Huntington’s disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms is inversely correlated with the size of the inherited CAG repeat, which expands further in brain regions due to somatic repeat instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset is also influenced by genetic variation at many loci, the majority of which encode genes involved in DNA maintenance/repair processes and repeat instability. Objective: We performed a complementary association analysis to determine whether variants in the X chromosome modify HD. Methods: We imputed SNPs on chromosome X for ∼9,000 HD subjects of European ancestry and performed an X chromosome-wide association study (XWAS) to test for association with age-at-onset corrected for inherited CAG repeat length. Results: In a mixed effects model XWAS analysis of all subjects (males and females), assuming random X-inactivation in females, no genome-wide significant onset modification signal was found. However, suggestive significant association signals were detected at Xq12 (top SNP, rs59098970; p-value, 1.4E-6), near moesin (MSN), in a region devoid of DNA maintenance genes. Additional suggestive signals not involving DNA repair genes were observed in male- and female-only analyses at other locations. Conclusion: Although not genome-wide significant, potentially due to small effect size compared to the power of the current study, our data leave open the possibility of modification of HD by a non-DNA repair process. Our XWAS results are publicly available at the updated GEM EURO 9K website hosted at https://www.hdinhd.org/ for browsing, pathway analysis, and data download.

Sex contribution to average age at onset of Huntington’s disease depends on the number of (CAG)n repeats

“…Recently, variants within the MSH3 / DHFR locus—a proven source of the dynamic mutation instability in finally differentiated brain tissue 19 —have been found to be stronger modifiers of the diagnostic motor signs in women when analyses were set as sex-specific 11 . Moreover, X-chromosome-wide association study (XWAS) found a variant close to the moesin gene potentially modifying AO 36 . Differences in AO of HD between genders have previously been reported for carriers of different genotypes within the APOE gene 24 .…”

Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases

“…For example, since RPA4 but not RPA1, RPA2, or RPA3, preferentially associates with MSH3 (Figure 4C), one can imagine Alt-RPA working with MutSβ, (MSH2-MSH3) to mediate CAG repeat expansions, possibly through retention of the excess repeats in poorly repaired slip-outs (Figure 2). Our data now reveal RPA1-4 as key players in CAG instability, despite the fact that RPA1-4, like MSH2, were not identified in the disease modifier screens [11][12][13][14][15]128 . Beyond repeat diseases, these RPA subunit BioID data provide a myriad of potential Alt-RPA↔RPA interactions which can shed light on a many metabolic pathways.…”