TY  - JOUR
AU  - Le Grand, Quentin
AU  - Tsuchida, Ami
AU  - Koch, Alexandra
AU  - Imtiaz, Mohammed Aslam
AU  - Aziz, N Ahmad
AU  - Vigneron, Chloé
AU  - Zago, Laure
AU  - Lathrop, Mark
AU  - Dubrac, Alexandre
AU  - Couffinhal, Thierry
AU  - Crivello, Fabrice
AU  - Matthews, Paul M
AU  - Mishra, Aniket
AU  - Breteler, Monique M B
AU  - Tzourio, Christophe
AU  - Debette, Stéphanie
TI  - Diffusion imaging genomics provides novel insight into early mechanisms of cerebral small vessel disease.
JO  - Molecular psychiatry
VL  - 29
IS  - 11
SN  - 1359-4184
CY  - London
PB  - Macmillan
M1  - DZNE-2024-00740
SP  - 3567 - 3579
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Cerebral Small Vessel Diseases: genetics
KW  - Genome-Wide Association Study: methods
KW  - Female
KW  - Male
KW  - Adult
KW  - Middle Aged
KW  - Aged
KW  - Diffusion Tensor Imaging: methods
KW  - White Matter: diagnostic imaging
KW  - White Matter: metabolism
KW  - Brain: metabolism
KW  - Young Adult
KW  - Aged, 80 and over
KW  - Genomics: methods
KW  - Adolescent
KW  - Diffusion Magnetic Resonance Imaging: methods
KW  - Polymorphism, Single Nucleotide: genetics
KW  - Neurites: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11541005
C6  - pmid:38811690
DO  - DOI:10.1038/s41380-024-02604-7
UR  - https://pub.dzne.de/record/270140
ER  -