Diffusion imaging genomics provides novel insight into early mechanisms of cerebral small vessel disease.

Autor: Le Grand Q; University of Bordeaux, INSERM, Bordeaux Population Health research center, UMR1219, F-33000, Bordeaux, France.; Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Tsuchida A; University of Bordeaux, INSERM, Bordeaux Population Health research center, UMR1219, F-33000, Bordeaux, France.; University of Bordeaux, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France.; CNRS, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France.; CEA, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France., Koch A; Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Imtiaz MA; Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Aziz NA; Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.; Department of Neurology, Faculty of Medicine, University of Bonn, Bonn, Germany., Vigneron C; University of Bordeaux, INSERM, Bordeaux Population Health research center, UMR1219, F-33000, Bordeaux, France., Zago L; University of Bordeaux, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France.; CNRS, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France.; CEA, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France., Lathrop M; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, Montreal, QC, H3A 0G1, Canada., Dubrac A; Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada.; Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC, Canada.; Département d'Ophtalmologie, Université de Montréal, Montréal, QC, Canada., Couffinhal T; University of Bordeaux, INSERM, Biologie des maladies cardiovasculaires, U1034, F-33600, Pessac, France., Crivello F; University of Bordeaux, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France.; CNRS, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France.; CEA, Institute of Neurodegenerative Diseases, UMR5293, Neurofunctional Imaging Group, F-33000, Bordeaux, France., Matthews PM; UK Dementia Research Institute and Department of Brain Sciences, Imperial College, London, UK., Mishra A; University of Bordeaux, INSERM, Bordeaux Population Health research center, UMR1219, F-33000, Bordeaux, France., Breteler MMB; Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.; Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany., Tzourio C; University of Bordeaux, INSERM, Bordeaux Population Health research center, UMR1219, F-33000, Bordeaux, France.; Bordeaux University Hospital, Department of Medical Informatics, F-33000, Bordeaux, France., Debette S; University of Bordeaux, INSERM, Bordeaux Population Health research center, UMR1219, F-33000, Bordeaux, France. stephanie.debette@u-bordeaux.fr.; Bordeaux University Hospital, Department of Neurology, Institute for Neurodegenerative Diseases, F-33000, Bordeaux, France. stephanie.debette@u-bordeaux.fr.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Nov; Vol. 29 (11), pp. 3567-3579. Date of Electronic Publication: 2024 May 29.
DOI: 10.1038/s41380-024-02604-7
Abstrakt: Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.
(© 2024. The Author(s).)
Databáze: MEDLINE
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