Genome-wide profiling of short tandem repeat somatic instability reveals associations with age, sex and brain-related traits

Short tandem repeats (STRs) are highly abundant in the human genome and their age-related somatic instability is emerging as a pivotal pathomechanism in repeat expansion disorders. Nevertheless, currently no analysis tool exists for genome-wide profiling of STR somatic instability. Here, we present searchSTR, a novel computational framework that enables accurate STR genotyping and somatic instability quantification from both whole-genome and targeted sequencing data. Applying this approach, we analyzed STR variants from whole-genome sequencing data of the 1000 Genomes Project (n=3,202) and targeted deep-sequencing data of the population-based Rhineland Study (n=2,974). We provide a comprehensive multiancestry genome-wide reference panel of STR variants and their somatic instability, covering more than 1.4 million STRs across 26 populations. Remarkably, STR somatic instability at many loci was robustly associated with age, sex, brain morphology and markers of neurodegeneration. These findings reveal a crucial role for STR somatic instability as an age-dependent modifier of brain structure.