Fig. 3: Variation in genetic influences on 17 unstable STRs.

a, Genomic context, population frequencies (freq) among 420,522 unrelated European-ancestry UKB participants, associations (assoc.) with MSH2 and MSH3 variants and age, and the relative contributions of genetic modifiers of instability of 17 STRs. Prom., promoter. The relative contributions of five genetic modifier loci were estimated using local heritability analyses for STRs with sufficient signal (specifically, local heritability z-score > 2.5 for at least one of the five modifiers). b, The mean lengths of long alleles among UKB participants heterozygous for a long allele (based on imputation; from left to right, n = 155,291, 81,387, 257,934 and 240,294), stratified by age quintile and by genotype of an instability-modifying haplotype. The two STRs with the strongest age association and the two with the strongest genetic associations are shown. Error bars show the 95% CIs. c, Associations of modifier haplotypes of DNA-repair and DNA-damage-response genes with blood instability of 10 STRs (including HTT¹⁸) and with hastening of four HD clinical phenotypes¹⁸. The table cells contain z statistics from association analyses; associations with P < 0.05, 0.01 and 0.001 are shaded in green or purple depending on whether the effect size agrees or disagrees with the consensus effect direction (cons. effect dir.) for blood instability. The effect sign in each table cell corresponds to the direction of effect on repeat instability: a positive effect indicates that the alternate allele associated with increased somatic expansion or hastening of an HD clinical landmark. TFC6, a score of 6 on the 13-point total functional capacity scale; TMS, total motor score.