Tandem Repeat Polymorphisms Are Associated with Brain Structure: Results of Two Large Population-based Studies

Although genome-wide association studies (GWAS) have uncovered many genetic variants linked to brain structure, much of its heritability remains unexplained. Short tandem repeats (STRs), which are rarely considered in GWAS, may contribute to this “missing heritability”. Using targeted deep sequencing, we systematically assessed the relationship between ∼3000 polymorphic STRs and brain imaging-derived phenotypes across 2958 participants of the Rhineland Study. Expansion of an intronic CA repeat in PRR14L was associated with larger thalamic volume (standardized β [95% CI]=0.15 [0.06–0.24]), while AATG repeat polymorphisms in NADK were associated with reduced subcortical gray matter volume (–0.05 [–0.08 to –0.01]). Both associations replicated in the UK Biobank cohort (N=38879). Beyond single loci, higher polygenic burden of moderate STR expansions was associated with increased total brain, gray matter, supratentorial, and thalamic volumes. Our findings indicate that moderate STR expansions are region-specific determinants of brain morphology and suggest that STR variability may have evolved to enhance neuroanatomical plasticity and cognitive function.