Genetic analyses of diffusion MRI phenotypes: a lifespan exploration of cSVD determinants

Abstract

AbstractBackgroundCerebral small vessel disease (cSVD) is a leading cause of vascular cognitive impairment and dementia. Mounting evidence suggests that early life factors contribute to cSVD. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI‐marker of cSVD in older age, were recently found to show strong associations with white matter microstructure on diffusion tensor imaging (DTI) already in young adults in their twenties. Here we aimed to use multi‐shell diffusion imaging to further explore genetic determinants of white matter microstructure across the adult lifespan and its relation with cSVD.MethodIn 1,758 participants (mean age: 22.1 [18 to 35] years) from the i‐Share student cohort who underwent multi‐shell diffusion imaging, we used neurite orientation dispersion and density imaging (NODDI) to generate tissue‐based markers of white matter microstructure including neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) in 28 brain regions. We ran genome‐wide association studies (GWAS) of all 84 NODDI markers in i‐Share and looked up genome‐wide significant variants in UK Biobank (N = 33,224, mean age: 64.3 [45 to 82] years) to identify loci with a lifecourse effect on these phenotypes. Next, we studied the association of genetically determined WMH volume and blood pressure with NODDI phenotypes in i‐Share using Mendelian randomization (MR).ResultThis first GWAS of 84 NODDI phenotypes in young adults identified 21 genome‐wide significant loci. Three of them, associated mostly with NDI, also showed significant association with NODDI phenotypes in middle‐aged to older UK Biobank participants, including a known WMH locus near VCAN, a cerebrovascular matrisome gene. Using MR we found that genetically determined WMH, previously shown to predict Alzheimer‐type dementia, was associated with lower NDI in young adults. In contrast, genetically determined blood pressure, although an important risk factor for WMH volume, did not show any significant association with NODDI phenotypes in young adults.ConclusionOur results suggest that NODDI markers, especially NDI, have a substantial genetic component already in early adulthood and may inform early mechanisms underlying the vascular contribution to dementia. Replication of these findings in additional CHARGE cohorts (Rhineland study, Framingham Heart study) is underway.