ArticleBrain : a journal of neurology2023
Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.
Article in Brain : a journal of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
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- A latent genetic factor underlies multiple component phenotypes of cerebral small vessel disease.BMC neuroscience · 2026Article
- A spatially resolved genomic-molecular atlas of human white-matter microstructure.medRxiv : the preprint server for health sciences · 2026Article
- Multiomics Profiling Supports Cathepsin B as a Protective Factor in Cerebral Small Vessel Disease.Research square · 2026Article
- PRISM-xQTL: Pleiotropic Relationships Integrated with System-level Multiomic QTL analysis for causal genes and molecular mediators in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Promoter hypomethylation ofFrontiers in genetics · 2026Article
- Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease.Nature aging · 2025Article
- Study on Abnormal Angiogenesis in Moyamoya Disease via Mitochondrial D-Loop Methylation.Brain and behavior · 2025Article
- Innovative machine learning approach for liver fibrosis and disease severity evaluation in MAFLD patients using MRI fat content analysis.Clinical and experimental medicine · 2025Article
- Epigenetic clocks and DNA methylation biomarkers of brain health and disease.Nature reviews. Neurology · 2025Review
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- Neighborhood environment associations with cognitive function and structural brain measures in older African Americans.BMC medicine · 2025Article
- Novel imaging diagnosis of neuropsychiatric systemic lupus erythematosus using topological data analysis: A retrospective study.PloS one · 2025Article
- Inhibition of brain glutamate carboxypeptidase II (GCPII) to enhance cognitive function.Advances in pharmacology (San Diego, Calif.) · 2025Review
- Intermediate endophenotypes and epigenetic mechanisms of psychiatric disorders.Imaging neuroscience (Cambridge, Mass.) · 2025Article
- A scoping review of statistical methods to investigate colocalization between genetic associations and microRNA expression in osteoarthritis.Osteoarthritis and cartilage open · 2024Article
- Imbalance of the von Willebrand Factor - ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S).Neurological research and practice · 2024Article
- Molecular profiling of frontal and occipital subcortical white matter hyperintensities in Alzheimer's disease.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
52 authors at 20 institutions in 8 countries.
Funding
Abstract
Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.
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