Shared genetic architecture of brain age gap across 30 cohorts worldwide

Authors

Vilte Baltramonaityte, Philippe Jawinski, Marlene Staginnus, Mina Shahisavandi, Boglarka Z Kovacs, Isabel K Schuurmans, Constantinos Constantinides, Ahmad R Hariri, Alexander Teumer, Amanda L Rodrigue, Ami Tsuchida, Amirhossein Manzouri, Andriana Karuk, Anna E Fürtjes, Annalisa Lella, Annchen R Knodt, Antonia Jüllig, Avshalom Caspi, Benedicto Crespo-Facorro, Brenda Wjh Penninx, Catharina Lavebratt, Christine Lochner, Clarissa L Yasuda, Dag Alnæs, Dan J Stein, Daniel H Mathalon, David C Glahn, Dennis Klose, Dylan J Kiltschewskij, Edith Pomarol-Clotet, Estela M Bruxel, Fabrice Crivello, Fernando Cendes, Gail Davies, Giovanni A Salum, Hans J Grabe, Heather J Zar, Henning Tiemeier, Henry Völzke, Hervé Lemaître, Iscia Lopes-Cendes, Ítalo Karmann Aventurato, Jean Shin, Jessica A Turner, Joanna M Wardlaw, John Blangero, Jonathan C Ipser, Judith M Ford, Kang Sim, Karen Sugden, Katharina Wittfeld, Kristina Salontaji, Kristoffer Nt Månsson, L Elliot Hong, Lars T Westlye, Lianne Schmaal, Lucas T Ito, Lucas Scárdua-Silva, Marcos L Santoro, María Alemany-Navarro, Mark E Bastin, Mary S Mufford, Melissa J Green, Murray J Cairns, Nadine Parker, Nathaniel W McGregor, Ole A Andreassen, Oliver Gruber, Oliver J Watkeys, Pedro M Pan, Peter Kochunov, Qian Hui Chew, Rafael Romero-Garcia, Raymond Salvador, Reremoana Theodore, Richie Poulton, Robin Bülow, Rodrigo A Bressan, Ryan L Muetzel, Sebastian Markett, Serena Defina, Sheri-Michelle Koopowitz, Shir Dahan, Simon R Cox, Sintia Belangero, So M Vijayakumar Kamalakannan, Sophia I Thomopoulos, Stefan Frenzel, Terrie E Moffitt, Theo Gm van Erp, Tomas Furmark, Tomas Paus, Uwe Völker, Vince D Calhoun, Yann Quidé, Younghwa Lee, Yuri Milaneschi, Zdenka Pausova, Paul M Thompson, Laura Km Han, Jean-Baptiste Pingault, James H Cole, Charlotte Am Cecil, Sarah E Medland, Danai Dima, Esther Walton

Abstract

medRxiv [Preprint]. 2025 Dec 27:2025.12.23.25342890. doi: 10.64898/2025.12.23.25342890.

ABSTRACT

Deviations from normative brain ageing trajectories are linked to a wide range of adverse health outcomes. A number of brain age prediction models have been developed, based on various neuroimaging modalities, machine learning algorithms, training samples, and age ranges. However, it remains unknown whether these models converge on a shared genetic liability, and whether capturing this shared signal could provide a more sensitive marker of brain health than any single model alone. We first conducted a new brain age gap (BAG) GWAS in a sample of 60,735 individuals across 29 cohorts worldwide, and then applied genomic structural equation modelling to examine the shared genetic variance between five prior BAG GWASs and our new analysis, using a single latent BAG factor (30 cohorts overall). All six BAG GWASs loaded onto a single factor, explaining 63% of the total genetic variance. We identified 19 independent SNPs associated with the BAG factor, including four novel associations. Genetically, the BAG factor was positively correlated with multiple traits, with blood pressure, smoking, longevity, autism, and sleep showing putatively causal effects. A polygenic score (PGS) for the BAG factor showed associations with phenotypic BAGs already in childhood, with stronger links observed in adulthood. Phenome-wide association analyses indicated that BAG factor PGS captured associations with more health traits than individual BAG PGSs. Our findings underscore the importance of considering the shared variance across different BAG constructs to identify robust correlates of poor brain health.

PMID:41480039 | PMC:PMC12755271 | DOI:10.64898/2025.12.23.25342890