Hieab Adams (Netherlands)
Erasmus MC Department of EpidemiologyAuthor Of 2 Presentations
GENOMICS OF PSMD, A NOVEL DTI MARKER OF SVD - BY THE CHARGE CONSORTIUM
Abstract
Background And Aims
Peak width of skeletonized mean diffusivity (PSMD) is a new fully automated diffusion tensor imaging (DTI) marker that showed clinically relevant changes in cerebral small vessel disease (SVD) and was suggested to be one of the earliest markers of brain aging across the adult lifespan. We conducted the first genome-wide association studies of PSMD to decipher its genetic underpinnings.
Methods
We included 55,988 stroke-free participants from 19 population-based cohorts (91.3% European). PSMD was generated using the same automated algorithm across cohorts. We tested association of genetic variants with log (PSMD) in each cohort followed by inverse-variance-weighted meta-analysis (with and without adjustment for total intracranial volume). We performed secondary association analyses stratified on age (age <35, 36-65, >65 years) and searched for shared genetic variation with vascular and neurological phenotypes using linkage disequilibrium-score regression.
Results
We identified 14 independent genome-wide significant associations across all association models. Half of these were known genome-wide risk loci for white matter hyperintensity (WMH) volume, 43% were shared with other DTI metrics (mean diffusivity [MD] or fractional anisotropy [FA]), and 36% were specific for PSMD. Genetic correlation of PSMD across age strata was high, although genome-wide significant loci partly differed across age groups. We found significant positive correlation of PSMD with WMH, MD, FA, any and ischemic stroke, deep intracerebral hemorrhage, systolic/diastolic blood pressure, type-2 diabetes.
Conclusions
Identified genetic risk variants and patterns of genetic correlation support the hypothesis that PSMD is reflecting underlying SVD, with a pattern across age-strata suggesting long-term progression.
Trial Registration Number
“Not applicable"
DECIPHERING THE GENOMICS OF DILATED PERIVASCULAR SPACE BURDEN
Abstract
Group Name
on behalf of the CHARGE consortium
Background And Aims
Dilated perivascular space (dPVS) burden is an emerging MRI-marker of cerebral small vessel disease (cSVD). We conducted a genome-wide association study of dPVS burden in 40,095 participants from 18 middle-aged to older population-based cohorts to decipher genetic underpinnings.
Methods
We tested association of genetic variants with the top quartile of white matter (WM), basal ganglia (BG), and hippocampal (HIP) dPVS burden distribution in each cohort followed by sample-size weighted meta-analysis. We explored shared genetic variation with other MRI-markers, putative risk factors, and neurological traits and conducted extensive functional exploration of identified dPVS loci using innovative bioinformatics approaches.
Results
We identified 24 genome-wide significant loci associated with extensive dPVS burden in older community-persons, primarily in WM. A weighted genetic risk score for WM dPVS burden was significantly associated with WM dPVS in young adults in their twenties. BG and HIP dPVS showed significant genetic correlation with high blood pressure, stroke (ischemic and hemorrhagic), and other MRI-cSVD markers. While some pleiotropy with vascular risk factors was observed, 2/3 of dPVS risk loci point to novel biological pathways, involving extracellular matrix, membrane transport, and developmental processes. Genome-wide significant dPVS loci were enriched in genes harboring causal mutations for monogenic white matter disease and genes expressed in brain endothelial cells. We used transcriptome-wide association studies to seek evidence for causal implication of specific genes underlying observed associations.
Conclusions
These findings shed new light on the biology underlying dPVS across the lifespan, with distinct mechanisms and clinical significance according to dPVS location.
Trial Registration Number
Not applicable