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000270140 1001_ $$0P:(DE-2719)9002736$$aLe Grand, Quentin$$b0$$eFirst author
000270140 245__ $$aDiffusion imaging genomics provides novel insight into early mechanisms of cerebral small vessel disease.
000270140 260__ $$aLondon$$bMacmillan$$c2024
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000270140 520__ $$aCerebral 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.
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000270140 650_2 $$2MeSH$$aHumans
000270140 650_2 $$2MeSH$$aCerebral Small Vessel Diseases: genetics
000270140 650_2 $$2MeSH$$aGenome-Wide Association Study: methods
000270140 650_2 $$2MeSH$$aFemale
000270140 650_2 $$2MeSH$$aMale
000270140 650_2 $$2MeSH$$aAdult
000270140 650_2 $$2MeSH$$aMiddle Aged
000270140 650_2 $$2MeSH$$aAged
000270140 650_2 $$2MeSH$$aDiffusion Tensor Imaging: methods
000270140 650_2 $$2MeSH$$aWhite Matter: diagnostic imaging
000270140 650_2 $$2MeSH$$aWhite Matter: metabolism
000270140 650_2 $$2MeSH$$aBrain: metabolism
000270140 650_2 $$2MeSH$$aYoung Adult
000270140 650_2 $$2MeSH$$aAged, 80 and over
000270140 650_2 $$2MeSH$$aGenomics: methods
000270140 650_2 $$2MeSH$$aAdolescent
000270140 650_2 $$2MeSH$$aDiffusion Magnetic Resonance Imaging: methods
000270140 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide: genetics
000270140 650_2 $$2MeSH$$aNeurites: metabolism
000270140 693__ $$0EXP:(DE-2719)Rhineland Study-20190321$$5EXP:(DE-2719)Rhineland Study-20190321$$eRhineland Study / Bonn$$x0
000270140 7001_ $$00000-0001-5160-6203$$aTsuchida, Ami$$b1
000270140 7001_ $$0P:(DE-2719)2810822$$aKoch, Alexandra$$b2$$udzne
000270140 7001_ $$0P:(DE-2719)9002347$$aImtiaz, Mohammed Aslam$$b3
000270140 7001_ $$0P:(DE-2719)2812578$$aAziz, N Ahmad$$b4
000270140 7001_ $$aVigneron, Chloé$$b5
000270140 7001_ $$aZago, Laure$$b6
000270140 7001_ $$aLathrop, Mark$$b7
000270140 7001_ $$aDubrac, Alexandre$$b8
000270140 7001_ $$aCouffinhal, Thierry$$b9
000270140 7001_ $$00000-0001-6950-984X$$aCrivello, Fabrice$$b10
000270140 7001_ $$00000-0002-1619-8328$$aMatthews, Paul M$$b11
000270140 7001_ $$00000-0002-8141-1543$$aMishra, Aniket$$b12
000270140 7001_ $$0P:(DE-2719)2810403$$aBreteler, Monique M B$$b13
000270140 7001_ $$00000-0002-6517-2984$$aTzourio, Christophe$$b14
000270140 7001_ $$00000-0001-8675-7968$$aDebette, Stéphanie$$b15
000270140 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-024-02604-7$$n11$$p3567 - 3579$$tMolecular psychiatry$$v29$$x1359-4184$$y2024
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