Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI
Authors: Yang Yunju , Knol Maria J , Wang Ruiqi , Mishra Aniket , Liu Dan , Luciano Michelle , Teumer Alexander , Armstrong Nicola , Bis Joshua C , Jhun Min A , Li Shuo , Adams Hieab H H , Aziz Nasir Ahmad , Bastin Mark E , Bourgey Mathieu , Brody Jennifer A , Frenzel Stefan , Gottesman Rebecca F , Hosten Norbert , Hou Lifang , Kardia Sharon L R , Lohner Valerie , Marquis Pascale , Maniega Susana Muñoz , Satizabal Claudia L , Sorond Farzaneh A , Valdés Hernández Maria C , van Duijn Cornelia M , Vernooij Meike W , Wittfeld Katharina , Yang Qiong , Zhao Wei , Boerwinkle Eric , Levy Daniel , Deary Ian J , Jiang Jiyang , Mather Karen A , Mosley Thomas H , Psaty Bruce M , Sachdev Perminder S , Smith Jennifer A , Sotoodehnia Nona , DeCarli Charles S , Breteler Monique M B , Ikram M Arfan , Grabe Hans J , Wardlaw Joanna , Longstreth W T , Launer Lenore J , Seshadri Sudha , Debette Stephanie , Fornage Myriam 
Published: August 2022

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.