The impact of Short Tandem Repeats on grey matter brain imaging derived phenotypes in UK Biobank

We performed a genome-wide association study of 143,067 highly polymorphic short tandem repeats (STRs) with MRI brain grey matter volumes (GMVs) on 10,702 UK Biobank (UKB) participants, including 8,751 in the discovery stage and 1,701 in the replication analysis. STRs’ repeat lengths were estimated from the UKB whole-genome sequencing data using Expansion Hunter software. A total of 262 STRs reached genome-wide significance in the analyses of the autosomal and sex chromosomes’ ( P = 6.9 × 10−8) in association with MRI -GMVs. Replication in a second batch extraction in the UKB and linkage disequilibrium (LD) analyses confirmed 12 associations of five STRs with hippocampal, intra-calcarine cortex, and cerebellum volumes with no evidence of single nucleotide polymorphisms (SNP) in LD detected in the surrounding DNA regions. Our study highlights the importance of STR variants involved in the genetic architecture of grey matter volumes. ### Competing Interest Statement W.S. is funded by Johnson and Johnson. A.N.H. received funding from Johnson and Johnson, GlaxoSmithKline and Ono Pharma. B.S., E.A.K., P.P., K.Y.H., B.A.J.S. and T.H. are employed by Johnson and Johnson. M.H.B is employed by Foresite Labs. ### Funding Statement This study was funded by Janssen Research and Development Ltd of Johnson and Johnson ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UK Biobank Ethics Advisory Committee (EAC), as part of the Committee of the UK Biobank Board, has approved access to the UK Biobank genetic and clinical/phenotypic data. This research was conducted using the UK Biobank Resource under the approved projects 52293 and 15181. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.