Genome-wide analysis of brain age identifies 25 associated loci and unveils relationships with mental and physical health

Neuroimaging and machine learning are opening up new opportunities in studying biological aging mechanisms. In this field, ‘brain age gap’ has emerged as promising MRI-based biomarker quantifying the deviation between an individual’s biological and chronological age of the brain – an indicator of accelerated/decelerated aging. Here, we investigated the genetic architecture of brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in 32,634 UK Biobank individuals unveiled a 30% SNP-based heritability and highlighted 25 associated loci. Of these, 23 showed sign-consistency and 16 replicated in another 7,259 individuals. The leading locus encompasses MAPT , encoding the tau protein central to Alzheimer’s disease. Genetic correlations revealed relationships with various mental health (depression), physical health (diabetes), and socioeconomic variables (education). Mendelian Randomization indicated a causal role of enhanced blood pressure on accelerated brain aging. This work refines our understanding of genetically modulated brain aging and its implications for human health. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. UK Biobank also received funding from the Welsh Government, British Heart Foundation, Cancer Research UK and Diabetes UK. This publication was supported by LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig. LIFE was funded by means of the European Social Fund and the Free State of Saxony. ### 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: This research has been conducted using the UK Biobank Resource under Application Number 423032. UK Biobank received ethical approval from the National Research Ethics Service Committee North West-Haydock (reference 11/NW/0382). LIFE-Adult was approved by the Ethics Committee of the University of Leipzig (263-2009-14122009). 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 The individual-level data incorporated in this work have been obtained from the UK Biobank resource (). GWAS summary statistics for BAG will be made available at Zenodo () upon publication of this article.