Insights into the causes and consequences of DNA repeat expansions from 700,000 biobank participants

Expansions and contractions of tandem DNA repeats are a source of genetic variation in human populations and in human tissues: some expanded repeats cause inherited disorders, and some are also somatically unstable. We analyzed DNA sequence data, derived from the blood cells of >700,000 participants in UK Biobank and the All of Us Research Program, and developed new computational approaches to recognize, measure and learn from DNA-repeat instability at 15 highly polymorphic CAG-repeat loci. We found that expansion and contraction rates varied widely across these 15 loci, even for alleles of the same length; repeats at different loci also exhibited widely variable relative propensities to mutate in the germline versus the blood. The high somatic instability of TCF4 repeats enabled a genome-wide association analysis that identified seven loci at which inherited variants modulate TCF4 repeat instability in blood cells. Three of the implicated loci contained genes ( MSH3 , FAN1 , and PMS2 ) that also modulate Huntington's disease age-at-onset as well as somatic instability of the HTT repeat in blood; however, the specific genetic variants and their effects (instability-increasing or-decreasing) appeared to be tissue-specific and repeat-specific, suggesting that somatic mutation in different tissues-or of different repeats in the same tissue-proceeds independently and under the control of substantially different genetic variation. Additional modifier loci included DNA damage response genes ATAD5 and GADD45A . Analyzing DNA repeat expansions together with clinical data showed that inherited repeats in the 5' UTR of the glutaminase ( GLS) gene are associated with stage 5 chronic kidney disease (OR=14.0 [5.7-34.3]) and liver diseases (OR=3.0 [1.5-5.9]). These and other results point to the dynamics of DNA repeats in human populations and across the human lifespan.