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In this study, we systematically assessed the relationship between STR variations and brain imaging-derived phenotypes across the adult lifespan in the general population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used targeted deep sequencing to genotype approximately 3,000 polymorphic STRs across 2,958 individuals (mean age: 54.1 years, range: 30\u201390 years, 57.1% women) from the population-based Rhineland Study in Bonn, Germany. STR sizes at 2940 loci were estimated using ExpansionHunter v5, while 45 brain imaging-derived phenotypes were obtained from 3T T1-weighted MRI scans using the FreeSurfer processing pipeline. Associations between STR lengths and neuroimaging phenotypes were assessed using multiple linear regression models, adjusting for age, sex, population stratification, and other relevant covariates. Significant findings were independently assessed for directional consistency in the UK Biobank Imaging Substudy (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200938,879), leveraging available whole-genome sequencing data.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The expansion of an intronic AC repeat in\n                      <jats:italic>PRR14L<\/jats:italic>\n                      was associated with larger thalamic volume (standardized \u03b2 [95% CI]\u2009=\u20090.15 [0.06\u20130.24]), while AATG repeat polymorphisms in\n                      <jats:italic>NADK<\/jats:italic>\n                      were associated with reduced subcortical gray matter volume (\u20130.05 [\u20130.08 to \u2212\u20090.01]) and thalamic volume (\u20130.06 [\u20130.08 to \u2212\u20090.04]). These associations were directionally consistent in the UK Biobank cohort. Beyond single loci, higher polygenic burden of moderate STR expansions was associated with increased total brain, gray matter, supratentorial, and thalamic volumes (all multiple-testing\u2013corrected\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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. By leveraging large population-based cohorts, our study extends current understanding of how repetitive genomic elements contribute to inter-individual variation in brain structure beyond the effects of single-nucleotide variation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-026-01702-1","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T07:33:26Z","timestamp":1783323206000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tandem repeat polymorphisms are associated with brain structure: results of two large population-based studies"],"prefix":"10.1186","volume":"18","author":[{"given":"Richard","family":"Mantey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Touhidinia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanzeem","family":"Butt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Mokhtar","family":"Sidky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roohollah","family":"Sobhani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Estrada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Haendler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"De Domenico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc Daniel","family":"Beyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique Maria Bernadette","family":"Breteler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasir Ahmad","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"issue":"2","key":"1702_CR1","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.ajhg.2022.12.011","volume":"110","author":"A Abdellaoui","year":"2023","unstructured":"Abdellaoui A, Yengo L, Verweij KJH, Visscher PM. 15 years of GWAS discovery: Realizing the promise. 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