Diffusion kurtosis imaging (gen)omics unravels mechanisms of cerebral small vessel disease

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Traditional MRI-markers of cSVD are mainly detectable in older adults, but diffusion MRI (dMRI) measures of white matter microstructure can capture changes predisposing to cSVD earlier in life. In this study, we conducted large genomics and omics explorations of diffusion kurtosis imaging (DKI) dMRI markers, to better characterize the underlying biological mechanisms and explore their clinical relevance in relation to cognition, established cSVD MRI-markers and dementia. We conducted a genome-wide association study (GWAS) of DKI markers in the population-based Rhineland Study (N=5 930). We identified four genome-wide significant loci associated with DKI markers at chr3p25.1 (LINC00620-WNT7A), chr5q14.2 (VCAN), chr5q14.3 (VCAN-AS1) and chr8q24.21 (CCDC26), and 11 additional suggestive loci. Lead SNPs at chr5q14.3 and chr17q25.1 were associated with white matter hyperintensity volume, chr3p25.1 with white matter perivascular spaces, and chr7p11.2 with Alzheimer disease. Using a transcriptome-wide association study, we identified 17 genes with genetically determined expression associated with DKI markers, including 14 at the chr17q21.31 suggestive GWAS locus. Finally, we identified eight proteins associated with DKI markers in GWAS suggestive loci. Of these, MAD1L1, EGFR and GFAP were also associated with cognitive decline, and MAD1L1 with white matter hyperintensity volume. In conclusion, leveraging omics data, our study identified novel molecular determinants of DKI markers, providing important novel insights into life course determinants of cSVD, a leading cause of stroke and dementia.