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, Jin-Tai Yu

Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. · pubmed

Paper

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.

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Research summary

The paper explores the genetic mechanisms underlying brain glymphatic activity, which is relevant to neurodegenerative diseases and their relationship with aging. While it provides insights into genetic factors that may influence neurobiological processes across the lifespan, the findings are more focused on understanding the genetic architecture rather than directly addressing the root causes of aging or lifespan extension. Thus, while it contributes solid research to the field, its impact is limited in terms of advancing longevity research significantly.

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