Genome-wide association study unravels mechanisms of brain glymphatic activity

Shu-Yi Huang, Yi-Jun Ge, Peng Ren, Bang-Sheng Wu, Weikang Gong, Jing Du, Shi-Dong Chen, Ju-Jiao Kang, Qing Ma, Arun L. W. Bokde, Sylvane Desrivières, Hugh Garavan, Antoine Grigis, Herve Lemaitre, Michael N. Smolka, Sarah Hohmann, Jian-Feng Feng, Ya-Ru Zhang (), Wei Cheng () and Jin-Tai Yu ()
Additional contact information
Shu-Yi Huang: Fudan University
Yi-Jun Ge: Fudan University
Peng Ren: Fudan University
Bang-Sheng Wu: Fudan University
Weikang Gong: Fudan University
Jing Du: UNSW
Shi-Dong Chen: Fudan University
Ju-Jiao Kang: Fudan University
Qing Ma: Fudan University
Arun L. W. Bokde: Trinity College Dublin
Sylvane Desrivières: King’s College
Hugh Garavan: University of Vermont
Antoine Grigis: Université Paris-Saclay
Herve Lemaitre: Université Paris-Saclay
Michael N. Smolka: Technische Universität Dresden
Sarah Hohmann: Heidelberg University
Jian-Feng Feng: Fudan University
Ya-Ru Zhang: Fudan University
Wei Cheng: Fudan University
Jin-Tai Yu: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Brain glymphatic activity, as indicated by diffusion-tensor imaging analysis along the perivascular space (ALPS) index, is involved in developmental neuropsychiatric and neurodegenerative diseases, but its genetic architecture is poorly understood. Here, we identified 17 unique genome-wide significant loci and 161 candidate genes linked to the ALPS-indexes in a discovery sample of 31,021 individuals from the UK Biobank. Seven loci were replicated in two independent datasets. Genetic signals located at the 2p23.3 locus yielded significantly concordant effects in both young and aging cohorts. Genetic correlation and polygenic overlap analyses indicate a common underlying genetic mechanism between the ALPS-index, ventricular volumes, and cerebrospinal fluid tau levels, with GMNC (3q28) and C16orf95 (16q24.2) as the shared genetic basis. Our findings enhance the understanding of the genetics of the ALPS-index and provide insight for further research into the neurobiological mechanisms of glymphatic clearance activity across the lifespan and its relation to neuropsychiatric phenotypes.

Date: 2025
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DOI: 10.1038/s41467-024-55706-9

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