. 2023 Feb 13;146(2):492-506.

doi: 10.1093/brain/awac290.

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

Yunju Yang¹, Maria J Knol², Ruiqi Wang³, Aniket Mishra⁴, Dan Liu⁵, Michelle Luciano⁶, Alexander Teumer^{7

8

9}, Nicola Armstrong¹⁰, Joshua C Bis¹¹, Min A Jhun¹², Shuo Li³, Hieab H H Adams^{2

13}, Nasir Ahmad Aziz^{5

14}, Mark E Bastin¹⁵, Mathieu Bourgey^{16

17}, Jennifer A Brody¹¹, Stefan Frenzel¹⁸, Rebecca F Gottesman¹⁹, Norbert Hosten²⁰, Lifang Hou²¹, Sharon L R Kardia¹², Valerie Lohner⁵, Pascale Marquis^{16

17}, Susana Muñoz Maniega¹⁵, Claudia L Satizabal^{22

23

24}, Farzaneh A Sorond²⁵, Maria C Valdés Hernández¹⁵, Cornelia M van Duijn^{2

26}, Meike W Vernooij^{2

13}, Katharina Wittfeld^{18

27}, Qiong Yang^{3

23}, Wei Zhao¹², Eric Boerwinkle^{28

29}, Daniel Levy^{23

30}, Ian J Deary⁶, Jiyang Jiang³¹, Karen A Mather^{31

32}, Thomas H Mosley³³, Bruce M Psaty^{11

34}, Perminder S Sachdev^{31

35}, Jennifer A Smith¹², Nona Sotoodehnia¹¹, Charles S DeCarli³⁶, Monique M B Breteler^{5

37}, M Arfan Ikram², Hans J Grabe^{18

27}, Joanna Wardlaw¹⁵, W T Longstreth^{34

38}, Lenore J Launer³⁹, Sudha Seshadri^{22

23

24}, Stephanie Debette^{4

24

40}, Myriam Fornage^{1

28}

Affiliations

¹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
² Department of Epidemiology, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands.
³ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
⁴ University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, F-33000 Bordeaux, France.
⁵ Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
⁶ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
⁷ Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
⁸ German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald 17475, Germany.
⁹ Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, 15-269, Poland.
¹⁰ Mathematics and Statistics, Curtin University, 6845 Perth, Australia.
¹¹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 02115, USA.
¹² Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48104, USA.
¹³ Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands.
¹⁴ Department of Neurology, Faculty of Medicine, University of Bonn, 53127 Bonn, Germany.
¹⁵ Centre for Clinical Brain Sciences, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh, EH8 9AB, UK.
¹⁶ Canadian Centre for Computational Genomics, McGill University, Montréal, Quebec, Canada H3A 0G1.
¹⁷ Department for Human Genetics, McGill University Genome Centre, McGill University, Montréal, Quebec, Canada H3A 0G1.
¹⁸ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald 17475, Germany.
¹⁹ Stroke Branch, National Institutes of Neurological Disorders and Stroke, Bethesda, MD 20814, USA.
²⁰ Department of Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany.
²¹ Department of Preventive Medicine, Northwestern University, Chicago, IL 60611, USA.
²² Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases and Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX 78229, USA.
²³ The Framingham Heart Study, Framingham, MA 01701, USA.
²⁴ Department of Neurology, Boston University School of Medicine, Boston, MA 02115, USA.
²⁵ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
²⁶ Nuffield Department of Population Health, Oxford University, Oxford, OX3 7LF, UK.
²⁷ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, 17475 Rostock, Germany.
²⁸ Human Genetics Center, School of Public Health, University of Texas Health Science at Houston, Houston, TX 77030, USA.
²⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
³⁰ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.
³¹ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia.
³² Neuroscience Research Australia, Sydney, NSW 2031, Australia.
³³ The Memory Impairment Neurodegenerative Dementia (MIND) Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA.
³⁴ Department of Epidemiology, University of Washington, Seattle, WA 98104, USA.
³⁵ Neuropsychiatric Institute, The Prince of Wales Hospital, University of New South Wales, Randwick, NSW 2031, Australia.
³⁶ Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, CA 95816, USA.
³⁷ Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, 53127 Bonn, Germany.
³⁸ Department of Neurology, University of Washington, Seattle, WA 98104, USA.
³⁹ Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
⁴⁰ CHU de Bordeaux, Department of Neurology, F-33000 Bordeaux, France.

PMID: 35943854
PMCID: PMC9924914
DOI: 10.1093/brain/awac290

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

Yunju Yang et al. Brain. 2023.

. 2023 Feb 13;146(2):492-506.

doi: 10.1093/brain/awac290.

Authors

Affiliations

¹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
² Department of Epidemiology, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands.
³ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
⁴ University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, F-33000 Bordeaux, France.
⁵ Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
⁶ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
⁷ Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
⁸ German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald 17475, Germany.
⁹ Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, 15-269, Poland.
¹⁰ Mathematics and Statistics, Curtin University, 6845 Perth, Australia.
¹¹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 02115, USA.
¹² Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48104, USA.
¹³ Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands.
¹⁴ Department of Neurology, Faculty of Medicine, University of Bonn, 53127 Bonn, Germany.
¹⁵ Centre for Clinical Brain Sciences, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh, EH8 9AB, UK.
¹⁶ Canadian Centre for Computational Genomics, McGill University, Montréal, Quebec, Canada H3A 0G1.
¹⁷ Department for Human Genetics, McGill University Genome Centre, McGill University, Montréal, Quebec, Canada H3A 0G1.
¹⁸ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald 17475, Germany.
¹⁹ Stroke Branch, National Institutes of Neurological Disorders and Stroke, Bethesda, MD 20814, USA.
²⁰ Department of Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany.
²¹ Department of Preventive Medicine, Northwestern University, Chicago, IL 60611, USA.
²² Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases and Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX 78229, USA.
²³ The Framingham Heart Study, Framingham, MA 01701, USA.
²⁴ Department of Neurology, Boston University School of Medicine, Boston, MA 02115, USA.
²⁵ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
²⁶ Nuffield Department of Population Health, Oxford University, Oxford, OX3 7LF, UK.
²⁷ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, 17475 Rostock, Germany.
²⁸ Human Genetics Center, School of Public Health, University of Texas Health Science at Houston, Houston, TX 77030, USA.
²⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
³⁰ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.
³¹ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia.
³² Neuroscience Research Australia, Sydney, NSW 2031, Australia.
³³ The Memory Impairment Neurodegenerative Dementia (MIND) Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA.
³⁴ Department of Epidemiology, University of Washington, Seattle, WA 98104, USA.
³⁵ Neuropsychiatric Institute, The Prince of Wales Hospital, University of New South Wales, Randwick, NSW 2031, Australia.
³⁶ Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, CA 95816, USA.
³⁷ Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, 53127 Bonn, Germany.
³⁸ Department of Neurology, University of Washington, Seattle, WA 98104, USA.
³⁹ Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
⁴⁰ CHU de Bordeaux, Department of Neurology, F-33000 Bordeaux, France.

PMID: 35943854
PMCID: PMC9924914
DOI: 10.1093/brain/awac290

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.

Keywords: blood–brain barrier dysfunction; cerebral small vessel disease; epigenome-wide association study; integrative cross-omics analysis; white matter hyperintensities.

PubMed Disclaimer

Figures

**Figure 1**
**Overview of the study analytic scheme**.

**Figure 2**
**WMH-associated gene networks.** WMH-associated genes based on multi-molecular evidence are organized around the 19 key driver genes. (A) WMH-associated network consisting of four subnetworks—extracellular matrix (ECM) organization (*FMOD*, *COL3A1*, *SEPING1*, *SLC13A4* and *ISLR*); smooth muscle contraction (*TAGLN*); G-protein-coupled receptor ligand binding (*GAL*, *ECEL1*, *ESR1* and *NTS*) and cytokine signalling in immune system (*IFIT1* and *RTP4*). (B) WMH-associated network of lipid and lipoprotein metabolism (*KNG1*). Key drivers and associated gene networks identified in the Mergeomics analysis are coloured in orange. Neighbouring genes are grouped into networks and labelled in random colours.

See this image and copyright information in PMC

Cited by

The Genomic Intersection of Oligodendrocyte Dynamics in Schizophrenia and Aging Unravels Novel Pathological Mechanisms and Therapeutic Potentials.
Rivera AD, Normanton JR, Butt AM, Azim K. Rivera AD, et al. Int J Mol Sci. 2024 Apr 18;25(8):4452. doi: 10.3390/ijms25084452. Int J Mol Sci. 2024. PMID: 38674040 Free PMC article. Review.
Investigation of the causal relationship between inflammatory bowel disease and type 2 diabetes mellitus: a Mendelian randomization study.
Tang LT, Feng L, Cao HY, Shi R, Luo BB, Zhang YB, Liu YM, Zhang J, Li SY. Tang LT, et al. Front Genet. 2024 Feb 16;15:1325401. doi: 10.3389/fgene.2024.1325401. eCollection 2024. Front Genet. 2024. PMID: 38435063 Free PMC article.
Genetic Predisposition for White Matter Hyperintensities and Risk of Mild Cognitive Impairment and Alzheimer's Disease: Results from the HELIAD Study.
Sampatakakis SN, Mourtzi N, Charisis S, Mamalaki E, Ntanasi E, Hatzimanolis A, Ramirez A, Lambert JC, Yannakoulia M, Kosmidis MH, Dardiotis E, Hadjigeorgiou G, Sakka P, Scarmeas N. Sampatakakis SN, et al. Curr Issues Mol Biol. 2024 Jan 22;46(1):934-947. doi: 10.3390/cimb46010060. Curr Issues Mol Biol. 2024. PMID: 38275674 Free PMC article.
Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes.
Van der Auwera S, Ameling S, Wittfeld K, Frenzel S, Bülow R, Nauck M, Völzke H, Völker U, Grabe HJ. Van der Auwera S, et al. Int J Mol Sci. 2024 Jan 10;25(2):887. doi: 10.3390/ijms25020887. Int J Mol Sci. 2024. PMID: 38255959 Free PMC article.
Assessing the causal effect of genetically predicted metabolites and metabolic pathways on stroke.
Zhang T, Cao Y, Zhao J, Yao J, Liu G. Zhang T, et al. J Transl Med. 2023 Nov 17;21(1):822. doi: 10.1186/s12967-023-04677-4. J Transl Med. 2023. PMID: 37978512 Free PMC article.

See all "Cited by" articles

References

1. Pantoni L. Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701. - PubMed
1. Wardlaw JM, Benveniste H, Williams A. Cerebral vascular dysfunctions detected in human small vessel disease and implications for preclinical studies. Annu Rev Physiol. 2022;84:409–434. - PubMed
1. Carmelli D, DeCarli C, Swan GE, et al. . Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke. 1998;29:1177–1181. - PubMed
1. Atwood LD, Wolf PA, Heard-Costa NL, et al. . Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke. 2004;35:1609–1613. - PubMed
1. Kochunov P, Glahn D, Winkler A, et al. . Analysis of genetic variability and whole genome linkage of whole-brain, subcortical, and ependymal hyperintense white matter volume. Stroke. 2009;40:3685–3690. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

Affiliations

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous