Home LiteratureArticle Details
PMID: 35943854 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

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

Brain : a journal of neurology ·Vol. 146 ·No. 2 ·2023-00-13 ·Pages 492-506

Yang Y, Knol MJ, Wang R, Mishra A, Liu D, Luciano M, Teumer A, Armstrong N, Bis JC, Jhun MA, Li S, Adams HHH, Aziz NA, Bastin ME, Bourgey M, Brody JA, Frenzel S, Gottesman RF, Hosten N, Hou L, Kardia SLR, Lohner V, Marquis P, Maniega SM, Satizabal CL, Sorond FA, Valdés Hernández MC, van Duijn CM, Vernooij MW, Wittfeld K, Yang Q, Zhao W, Boerwinkle E, Levy D, Deary IJ, Jiang J, Mather KA, Mosley TH, Psaty BM, Sachdev PS, Smith JA, Sotoodehnia N, DeCarli CS, Breteler MMB, Ikram MA, Grabe HJ, Wardlaw J, Longstreth WT, Launer LJ, Seshadri S, Debette S, Fornage M

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
MeSH Terms
Middle Aged Humans Aged White Matter/diagnostic imaging Genome-Wide Association Study/methods Brain/diagnostic imaging DNA Methylation/genetics Magnetic Resonance Imaging Epigenesis, Genetic Protein-Arginine N-Methyltransferases Repressor Proteins
Chemicals
PRMT1 protein, human Protein-Arginine N-Methyltransferases Repressor Proteins
Authors & Affiliations
52 authors, click to expand affiliations / ORCID
Yang Yunju ORCID
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
Knol Maria J ORCID
Department of Epidemiology, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands.
Wang Ruiqi
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Mishra Aniket
University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, F-33000 Bordeaux, France.
Liu Dan
Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
Luciano Michelle
Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
Teumer Alexander
Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany. | German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald 17475, Germany. | Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, 15-269, Poland.
Armstrong Nicola
Mathematics and Statistics, Curtin University, 6845 Perth, Australia.
Bis Joshua C
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 02115, USA.
Jhun Min A
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48104, USA.
Li Shuo
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Adams Hieab H H
Department of Epidemiology, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands. | Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands.
Aziz Nasir Ahmad
Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. | Department of Neurology, Faculty of Medicine, University of Bonn, 53127 Bonn, Germany.
Bastin Mark E
Centre for Clinical Brain Sciences, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh, EH8 9AB, UK.
Bourgey Mathieu ORCID
Canadian Centre for Computational Genomics, McGill University, Montréal, Quebec, Canada H3A 0G1. | Department for Human Genetics, McGill University Genome Centre, McGill University, Montréal, Quebec, Canada H3A 0G1.
Brody Jennifer A
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 02115, USA.
Frenzel Stefan
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald 17475, Germany.
Gottesman Rebecca F
Stroke Branch, National Institutes of Neurological Disorders and Stroke, Bethesda, MD 20814, USA.
Hosten Norbert
Department of Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany.
Hou Lifang
Department of Preventive Medicine, Northwestern University, Chicago, IL 60611, USA.
Kardia Sharon L R
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48104, USA.
Lohner Valerie
Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
Marquis Pascale
Canadian Centre for Computational Genomics, McGill University, Montréal, Quebec, Canada H3A 0G1. | Department for Human Genetics, McGill University Genome Centre, McGill University, Montréal, Quebec, Canada H3A 0G1.
Maniega Susana Muñoz
Centre for Clinical Brain Sciences, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh, EH8 9AB, UK.
Satizabal Claudia L
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases and Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX 78229, USA. | The Framingham Heart Study, Framingham, MA 01701, USA. | Department of Neurology, Boston University School of Medicine, Boston, MA 02115, USA.
Sorond Farzaneh A
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Valdés Hernández Maria C
Centre for Clinical Brain Sciences, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh, EH8 9AB, UK.
van Duijn Cornelia M ORCID
Department of Epidemiology, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands. | Nuffield Department of Population Health, Oxford University, Oxford, OX3 7LF, UK.
Vernooij Meike W ORCID
Department of Epidemiology, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands. | Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands.
Wittfeld Katharina
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald 17475, Germany. | German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, 17475 Rostock, Germany.
Yang Qiong ORCID
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. | The Framingham Heart Study, Framingham, MA 01701, USA.
Zhao Wei
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48104, USA.
Boerwinkle Eric
Human Genetics Center, School of Public Health, University of Texas Health Science at Houston, Houston, TX 77030, USA. | Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Levy Daniel
The Framingham Heart Study, Framingham, MA 01701, USA. | Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.
Deary Ian J
Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
Jiang Jiyang
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia.
Mather Karen A ORCID
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia. | Neuroscience Research Australia, Sydney, NSW 2031, Australia.
Mosley Thomas H
The Memory Impairment Neurodegenerative Dementia (MIND) Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Psaty Bruce M
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 02115, USA. | Department of Epidemiology, University of Washington, Seattle, WA 98104, USA.
Sachdev Perminder S ORCID
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia. | Neuropsychiatric Institute, The Prince of Wales Hospital, University of New South Wales, Randwick, NSW 2031, Australia.
Smith Jennifer A ORCID
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48104, USA.
Sotoodehnia Nona
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 02115, USA.
DeCarli Charles S
Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, CA 95816, USA.
Breteler Monique M B
Population Health Sciences, German Centre for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. | Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, 53127 Bonn, Germany.
Ikram M Arfan
Department of Epidemiology, Erasmus MC University Medical Center, 3015 GD, Rotterdam, The Netherlands.
Grabe Hans J
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald 17475, Germany. | German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, 17475 Rostock, Germany.
Wardlaw Joanna
Centre for Clinical Brain Sciences, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh, EH8 9AB, UK.
Longstreth W T
Department of Epidemiology, University of Washington, Seattle, WA 98104, USA. | Department of Neurology, University of Washington, Seattle, WA 98104, USA.
Launer Lenore J
Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
Seshadri Sudha
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases and Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX 78229, USA. | The Framingham Heart Study, Framingham, MA 01701, USA. | Department of Neurology, Boston University School of Medicine, Boston, MA 02115, USA.
Debette Stephanie ORCID
University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, F-33000 Bordeaux, France. | Department of Neurology, Boston University School of Medicine, Boston, MA 02115, USA. | CHU de Bordeaux, Department of Neurology, F-33000 Bordeaux, France.
Fornage Myriam
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA. | Human Genetics Center, School of Public Health, University of Texas Health Science at Houston, Houston, TX 77030, USA.
References (137)
137 references, click to expand
  1. Severe hypomyelination associated with increased levels of N-acetylaspartylglutamate in CSF.
    Neurology. 2004 May 11;62(9):1503-8 PMID: 15136672
  2. Interindividual methylomic variation across blood, cortex, and cerebellum: implications for epigenetic studies of neurological and neuropsychiatric phenotypes.
    Epigenetics. 2015;10(11):1024-32 PMID: 26457534
  3. Analysis of genetic variability and whole genome linkage of whole-brain, subcortical, and ependymal hyperintense white matter volume.
    Stroke. 2009 Dec;40(12):3685-90 PMID: 19834011
  4. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards.
    Database (Oxford). 2017 Jan 1;2017: PMID: 28605766
  5. An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome.
    Nat Neurosci. 2017 Oct;20(10):1418-1426 PMID: 28869584
  6. PharmOmics: A species- and tissue-specific drug signature database and gene-network-based drug repositioning tool.
    iScience. 2022 Mar 10;25(4):104052 PMID: 35345455
  7. DNA methylation arrays as surrogate measures of cell mixture distribution.
    BMC Bioinformatics. 2012 May 08;13:86 PMID: 22568884
  8. Burden of Dilated Perivascular Spaces, an Emerging Marker of Cerebral Small Vessel Disease, Is Highly Heritable.
    Stroke. 2018 Feb;49(2):282-287 PMID: 29311265
  9. Evaluation of asymmetric dimethylarginine and homocysteine in microangiopathy-related cerebral damage.
    Am J Hypertens. 2009 Mar;22(3):257-62 PMID: 19057516
  10. DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.
    Am J Hum Genet. 2017 Dec 7;101(6):888-902 PMID: 29198723
  11. The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function.
    Nat Rev Mol Cell Biol. 2011 Jun 23;12(7):413-26 PMID: 21697900
  12. Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: systematic review and meta-analysis.
    Cerebrovasc Dis. 2014;37(1):64-75 PMID: 24401164
  13. Aminoacyl-tRNA synthetases as therapeutic targets.
    Nat Rev Drug Discov. 2019 Aug;18(8):629-650 PMID: 31073243
  14. Tight junction proteins at the blood-brain barrier: far more than claudin-5.
    Cell Mol Life Sci. 2019 May;76(10):1987-2002 PMID: 30734065
  15. Brain aging, cognition in youth and old age and vascular disease in the Lothian Birth Cohort 1936: rationale, design and methodology of the imaging protocol.
    Int J Stroke. 2011 Dec;6(6):547-59 PMID: 22111801
  16. The EWAS Catalog: a database of epigenome-wide association studies.
    Wellcome Open Res. 2022 Feb 4;7:41 PMID: 35592546
  17. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins.
    Stroke. 1998 Jun;29(6):1177-81 PMID: 9626291
  18. The transporter and permeability interactions of asymmetric dimethylarginine (ADMA) and L-arginine with the human blood-brain barrier in vitro.
    Brain Res. 2016 Oct 1;1648(Pt A):232-242 PMID: 27431938
  19. Cohort profile: the study of health in Pomerania.
    Int J Epidemiol. 2011 Apr;40(2):294-307 PMID: 20167617
  20. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators.
    Am J Epidemiol. 2013 Oct 1;178(7):1177-84 PMID: 23863760
  21. The Cardiovascular Health Study: design and rationale.
    Ann Epidemiol. 1991 Feb;1(3):263-76 PMID: 1669507
  22. Expression profiles analysis reveals an integrated miRNA-lncRNA signature to predict survival in ovarian cancer patients with wild-type BRCA1/2.
    Oncotarget. 2017 Jul 26;8(40):68483-68492 PMID: 28978132
  23. Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.
    Stroke. 2018 Aug;49(8):1812-1819 PMID: 30002152
  24. Methylomics of gene expression in human monocytes.
    Hum Mol Genet. 2013 Dec 15;22(24):5065-74 PMID: 23900078
  25. Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol.
    Brain. 2020 Feb 1;143(2):597-610 PMID: 31968102
  26. Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis.
    JAMA Neurol. 2019 Jan 1;76(1):81-94 PMID: 30422209
  27. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.
    Nat Genet. 2019 Jan;51(1):51-62 PMID: 30578418
  28. Heritability of leukoaraiosis in hypertensive sibships.
    Hypertension. 2004 Feb;43(2):483-7 PMID: 14718359
  29. Large-scale GWAS reveals genetic architecture of brain white matter microstructure and genetic overlap with cognitive and mental health traits (n = 17,706).
    Mol Psychiatry. 2021 Aug;26(8):3943-3955 PMID: 31666681
  30. Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury.
    Nat Commun. 2016 Jan 27;7:10523 PMID: 26813496
  31. Knockdown of long noncoding RNA CCDC144NL-AS1 attenuates migration and invasion phenotypes in endometrial stromal cells from endometriosis†.
    Biol Reprod. 2019 Apr 1;100(4):939-949 PMID: 30496345
  32. Perspective on the Alzheimer's disease neuroimaging initiative: progress report and future plans.
    Alzheimers Dement. 2010 May;6(3):199-201 PMID: 20451867
  33. ADMA: A Key Player in the Relationship between Vascular Dysfunction and Inflammation in Atherosclerosis.
    J Clin Med. 2020 Sep 20;9(9): PMID: 32962225
  34. Epigenetics: molecular mechanisms and implications for disease.
    Trends Mol Med. 2010 Jan;16(1):7-16 PMID: 20022812
  35. Interethnic analyses of blood pressure loci in populations of East Asian and European descent.
    Nat Commun. 2018 Nov 28;9(1):5052 PMID: 30487518
  36. Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits.
    Acta Neuropathol Commun. 2014 Aug 13;2:96 PMID: 25190493
  37. Mergeomics: a web server for identifying pathological pathways, networks, and key regulators via multidimensional data integration.
    BMC Genomics. 2016 Sep 09;17(1):722 PMID: 27612452
  38. Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension: a randomized, double-blind and placebo-controlled clinical trial.
    Hypertens Res. 2019 May;42(5):717-729 PMID: 30552406
  39. De novo identification of differentially methylated regions in the human genome.
    Epigenetics Chromatin. 2015 Jan 27;8:6 PMID: 25972926
  40. ADMA as a possible marker of endothelial damage. A study in young asymptomatic patients with cerebral small vessel disease.
    Sci Rep. 2019 Oct 2;9(1):14207 PMID: 31578412
  41. An integrative genomics approach to the reconstruction of gene networks in segregating populations.
    Cytogenet Genome Res. 2004;105(2-4):363-74 PMID: 15237224
  42. Matrix metalloproteinases and ADAMs in stroke.
    Cell Mol Life Sci. 2019 Aug;76(16):3117-3140 PMID: 31165904
  43. The MR-Base platform supports systematic causal inference across the human phenome.
    Elife. 2018 May 30;7: PMID: 29846171
  44. The Framingham Offspring Study. Design and preliminary data.
    Prev Med. 1975 Dec;4(4):518-25 PMID: 1208363
  45. The coagulation-fibrinolysis system in patients with leukoaraiosis and Binswanger disease.
    Arch Neurol. 2001 Oct;58(10):1620-5 PMID: 11594920
  46. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.
    Nat Genet. 2017 Mar;49(3):403-415 PMID: 28135244
  47. Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization.
    Neurology. 2010 Jan 19;74(3):201-9 PMID: 20042704
  48. Whole blood gene expression and white matter Hyperintensities.
    Mol Neurodegener. 2017 Sep 18;12(1):67 PMID: 28923099
  49. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats.
    Sci Transl Med. 2018 Jul 4;10(448): PMID: 29973407
  50. Construction of prognostic risk prediction model based on high-throughput sequencing expression profile data in childhood acute myeloid leukemia.
    Blood Cells Mol Dis. 2019 Jul;77:43-50 PMID: 30954792
  51. Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies.
    Annu Rev Physiol. 2022 Feb 10;84:409-434 PMID: 34699267
  52. Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226).
    Neurology. 2019 Feb 19;92(8):e749-e757 PMID: 30659137
  53. Leveraging Polygenic Functional Enrichment to Improve GWAS Power.
    Am J Hum Genet. 2019 Jan 3;104(1):65-75 PMID: 30595370
  54. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.
    Nature. 2000 May 25;405(6785):466-72 PMID: 10839543
  55. A Bayesian framework for multiple trait colocalization from summary association statistics.
    Bioinformatics. 2018 Aug 1;34(15):2538-2545 PMID: 29579179
  56. Cerebral small vessel disease genomics and its implications across the lifespan.
    Nat Commun. 2020 Dec 8;11(1):6285 PMID: 33293549
  57. LncRNA CCDC144NL-AS1 Serves as a Prognosis Biomarker for Non-small Cell Lung Cancer and Promotes Cellular Function by Targeting miR-490-3p.
    Mol Biotechnol. 2021 Oct;63(10):933-940 PMID: 34115289
  58. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  59. Discovery properties of genome-wide association signals from cumulatively combined data sets.
    Am J Epidemiol. 2009 Nov 15;170(10):1197-206 PMID: 19808636
  60. The actin cytoskeleton in endothelial cell phenotypes.
    Microvasc Res. 2009 Jan;77(1):53-63 PMID: 19028505
  61. Association of plasma ADMA levels with MRI markers of vascular brain injury: Framingham offspring study.
    Stroke. 2009 Sep;40(9):2959-64 PMID: 19644064
  62. Claudin-5: gatekeeper of neurological function.
    Fluids Barriers CNS. 2019 Jan 29;16(1):3 PMID: 30691500
  63. The GTEx Consortium atlas of genetic regulatory effects across human tissues.
    Science. 2020 Sep 11;369(6509):1318-1330 PMID: 32913098
  64. Glycogen synthase kinase-3 signaling in Alzheimer's disease.
    Biochim Biophys Acta Mol Cell Res. 2020 May;1867(5):118664 PMID: 32006534
  65. White matter hyperintensities, cognitive impairment and dementia: an update.
    Nat Rev Neurol. 2015 Mar;11(3):157-65 PMID: 25686760
  66. Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA.
    Mol Cell. 2016 Apr 21;62(2):157-168 PMID: 27105112
  67. coMET: visualisation of regional epigenome-wide association scan results and DNA co-methylation patterns.
    BMC Bioinformatics. 2015 Apr 28;16:131 PMID: 25928765
  68. Statins and cerebral hemodynamics.
    J Cereb Blood Flow Metab. 2012 Nov;32(11):1973-6 PMID: 22929438
  69. Comb-p: software for combining, analyzing, grouping and correcting spatially correlated P-values.
    Bioinformatics. 2012 Nov 15;28(22):2986-8 PMID: 22954632
  70. The Framingham study. An epidemiological approach to coronary heart disease.
    Circulation. 1966 Oct;34(4):553-5 PMID: 5921755
  71. Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline.
    Biol Psychiatry. 2022 Feb 15;91(4):389-398 PMID: 33838873
  72. A cross-population atlas of genetic associations for 220 human phenotypes.
    Nat Genet. 2021 Oct;53(10):1415-1424 PMID: 34594039
  73. The reactome pathway knowledgebase.
    Nucleic Acids Res. 2020 Jan 8;48(D1):D498-D503 PMID: 31691815
  74. Annotation of functional variation in personal genomes using RegulomeDB.
    Genome Res. 2012 Sep;22(9):1790-7 PMID: 22955989
  75. ESO Guideline on covert cerebral small vessel disease.
    Eur Stroke J. 2021 Jun;6(2):CXI-CLXII PMID: 34414301
  76. Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.
    Stroke. 2020 Jul;51(7):2111-2121 PMID: 32517579
  77. Cytoscape: a software environment for integrated models of biomolecular interaction networks.
    Genome Res. 2003 Nov;13(11):2498-504 PMID: 14597658
  78. Cerebral circulation: function and dysfunction in Alzheimer's disease.
    J Cardiovasc Pharmacol. 2015 Apr;65(4):317-24 PMID: 25384195
  79. PathCards: multi-source consolidation of human biological pathways.
    Database (Oxford). 2015 Feb 27;2015: PMID: 25725062
  80. The Molecular Signatures Database (MSigDB) hallmark gene set collection.
    Cell Syst. 2015 Dec 23;1(6):417-425 PMID: 26771021
  81. Mechanisms regulating endothelial permeability.
    Pulm Circ. 2014 Dec;4(4):535-51 PMID: 25610592
  82. The Lothian Birth Cohort 1936: a study to examine influences on cognitive ageing from age 11 to age 70 and beyond.
    BMC Geriatr. 2007 Dec 05;7:28 PMID: 18053258
  83. The Gene Ontology resource: enriching a GOld mine.
    Nucleic Acids Res. 2021 Jan 8;49(D1):D325-D334 PMID: 33290552
  84. The ARIC (Atherosclerosis Risk In Communities) Study: JACC Focus Seminar 3/8.
    J Am Coll Cardiol. 2021 Jun 15;77(23):2939-2959 PMID: 34112321
  85. Cognitive functioning in older twins: the Older Australian Twins Study.
    Australas J Ageing. 2011 Oct;30 Suppl 2:17-23 PMID: 22032766
  86. Genetic variation in white matter hyperintensity volume in the Framingham Study.
    Stroke. 2004 Jul;35(7):1609-13 PMID: 15143299
  87. Mergeomics: multidimensional data integration to identify pathogenic perturbations to biological systems.
    BMC Genomics. 2016 Nov 4;17(1):874 PMID: 27814671
  88. Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats.
    Neuropathol Appl Neurobiol. 2011 Dec;37(7):711-26 PMID: 21392049
  89. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  90. Familial aggregation of hypertension treatment and control in the Genetic Epidemiology Network of Arteriopathy (GENOA) study.
    Am J Med. 2004 May 15;116(10):676-81 PMID: 15121494
  91. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
    Nat Genet. 2020 Jul;52(7):669-679 PMID: 32514122
  92. Association of White Matter Hyperintensities With HIV Status and Vascular Risk Factors.
    Neurology. 2021 Apr 6;96(14):e1823-e1834 PMID: 33637630
  93. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges.
    Lancet Neurol. 2010 Jul;9(7):689-701 PMID: 20610345
  94. Assessing the effectiveness of statin therapy for alleviating cerebral small vessel disease progression in people ≥75 years of age.
    BMC Geriatr. 2020 Aug 17;20(1):292 PMID: 32807086
  95. METAL: fast and efficient meta-analysis of genomewide association scans.
    Bioinformatics. 2010 Sep 1;26(17):2190-1 PMID: 20616382
  96. Severe Hypomyelination and Developmental Defects Are Caused in Mice Lacking Protein Arginine Methyltransferase 1 (PRMT1) in the Central Nervous System.
    J Biol Chem. 2016 Jan 29;291(5):2237-45 PMID: 26637354
  97. Silent Cerebral Small-Vessel Disease Is Twice as Prevalent in Middle-Aged Individuals With Well-Controlled, Combination Antiretroviral Therapy-Treated Human Immunodeficiency Virus (HIV) Than in HIV-Uninfected Individuals.
    Clin Infect Dis. 2018 May 17;66(11):1762-1769 PMID: 29244126
  98. Long non-coding RNA CCDC144NL-AS1 sponges miR-143-3p and regulates MAP3K7 by acting as a competing endogenous RNA in gastric cancer.
    Cell Death Dis. 2020 Jul 9;11(7):521 PMID: 32647147
  99. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.
    Nat Genet. 2003 Mar;33 Suppl:245-54 PMID: 12610534
  100. Effect of pravastatin on cerebral infarcts and white matter lesions.
    Neurology. 2005 May 24;64(10):1807-9 PMID: 15911821
  101. The role of extracellular matrix alterations in mediating astrocyte damage and pericyte dysfunction in Alzheimer's disease: A comprehensive review.
    Eur J Neurosci. 2022 Nov;56(9):5453-5475 PMID: 34182602
  102. missMethyl: an R package for analyzing data from Illumina's HumanMethylation450 platform.
    Bioinformatics. 2016 Jan 15;32(2):286-8 PMID: 26424855
  103. The Rotterdam Scan Study: design update 2016 and main findings.
    Eur J Epidemiol. 2015 Dec;30(12):1299-315 PMID: 26650042
  104. Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease.
    Neurology. 2017 Jan 31;88(5):426-432 PMID: 28031395
  105. Elevated CSF N-acetylaspartylglutamate suggests specific molecular diagnostic abnormalities in patients with white matter diseases.
    Biochim Biophys Acta. 2010 Nov;1802(11):1112-7 PMID: 20637281
  106. LncRNA-CCDC144NL-AS1 Promotes the Development of Hepatocellular Carcinoma by Inducing WDR5 Expression via Sponging miR-940.
    J Hepatocell Carcinoma. 2021 May 03;8:333-348 PMID: 33977095
  107. Asymmetric dimethylarginine in cerebral small vessel disease.
    Stroke. 2007 Feb;38(2):411-3 PMID: 17204687
  108. The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination.
    Am J Epidemiol. 2007 Jun 1;165(11):1328-35 PMID: 17372189
  109. A comprehensive neuropsychiatric study of elderly twins: the Older Australian Twins Study.
    Twin Res Hum Genet. 2009 Dec;12(6):573-82 PMID: 19943720
  110. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells.
    Nat Biotechnol. 2012 Aug;30(8):783-91 PMID: 22729031
  111. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians.
    Nat Genet. 2011 Jun;43(6):531-8 PMID: 21572416
  112. Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants.
    Nat Commun. 2020 May 1;11(1):2175 PMID: 32358547
  113. S100B and ADMA in cerebral small vessel disease and cognitive dysfunction.
    J Neurol Sci. 2015 Jul 15;354(1-2):27-32 PMID: 25990800
  114. KEGG: kyoto encyclopedia of genes and genomes.
    Nucleic Acids Res. 2000 Jan 1;28(1):27-30 PMID: 10592173
  115. Methods for meta-analysis of multiple traits using GWAS summary statistics.
    Genet Epidemiol. 2018 Mar;42(2):134-145 PMID: 29226385
  116. Vascular tight junction disruption and angiogenesis in spontaneously hypertensive rat with neuroinflammatory white matter injury.
    Neurobiol Dis. 2018 Jun;114:95-110 PMID: 29486300
  117. Small vessel disease: mechanisms and clinical implications.
    Lancet Neurol. 2019 Jul;18(7):684-696 PMID: 31097385
  118. Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.
    Circ Cardiovasc Genet. 2015 Apr;8(2):398-409 PMID: 25663218
  119. EWAS Atlas: a curated knowledgebase of epigenome-wide association studies.
    Nucleic Acids Res. 2019 Jan 8;47(D1):D983-D988 PMID: 30364969
  120. Objectives, design and main findings until 2020 from the Rotterdam Study.
    Eur J Epidemiol. 2020 May;35(5):483-517 PMID: 32367290
  121. Cerebral small-vessel disease and decline in information processing speed, executive function and memory.
    Brain. 2005 Sep;128(Pt 9):2034-41 PMID: 15947059
  122. Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease.
    J Cereb Blood Flow Metab. 2015 Jun;35(6):1005-14 PMID: 25669904
  123. Genetic overlap of chronic obstructive pulmonary disease and cardiovascular disease-related traits: a large-scale genome-wide cross-trait analysis.
    Respir Res. 2019 Apr 2;20(1):64 PMID: 30940143
  124. Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.
    Brain. 2019 Apr 1;142(4):1009-1023 PMID: 30859180
  125. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray.
    Epigenetics. 2013 Feb;8(2):203-9 PMID: 23314698
  126. Association of prothrombotic status with markers of cerebral small vessel disease in elderly hypertensive patients.
    Am J Hypertens. 2012 Oct;25(10):1088-94 PMID: 22739806
  127. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
    N Engl J Med. 2009 Apr 23;360(17):1729-39 PMID: 19387015
  128. Brain endothelial TAK1 and NEMO safeguard the neurovascular unit.
    J Exp Med. 2015 Sep 21;212(10):1529-49 PMID: 26347470
  129. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.
    Nat Genet. 2018 Apr;50(4):524-537 PMID: 29531354
  130. Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease.
    Nat Commun. 2019 Sep 19;10(1):4267 PMID: 31537805
  131. CARDIA: study design, recruitment, and some characteristics of the examined subjects.
    J Clin Epidemiol. 1988;41(11):1105-16 PMID: 3204420
  132. Long Noncoding RNA CCDC144NL-AS1 Promotes the Oncogenicity of Osteosarcoma by Acting as a Molecular Sponge for microRNA-490-3p and Thereby Increasing HMGA2 Expression.
    Onco Targets Ther. 2021 Jan 06;14:1-13 PMID: 33442262
  133. Plasma levels of asymmetric dimethylarginine in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy.
    Cerebrovasc Dis. 2008;26(6):636-40 PMID: 18984949
  134. Protein arginine methylation of non-histone proteins and its role in diseases.
    Cell Cycle. 2014;13(1):32-41 PMID: 24296620
  135. Analysis of risk factors in patients with leukoaraiosis.
    Medicine (Baltimore). 2017 Feb;96(8):e6153 PMID: 28225497
  136. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study.
    Stroke. 2005 Jul;36(7):1410-4 PMID: 15905468
  137. Additional impact of morning haemostatic risk factors and morning blood pressure surge on stroke risk in older Japanese hypertensive patients.
    Eur Heart J. 2011 Mar;32(5):574-80 PMID: 21169614
Article Info
Journal
Brain : a journal of neurology
Abbr.
Brain
ISSN
1460-2156
DOI
10.1093/brain/awac290
Published
2023-00-13
Pages
492-506
Language
English
Region
England
NLM ID
0372537
PMCID
PMC9924914
Subset
IM
Grants
NIA NIH HHS · R01 AG054076 · United States
NIA NIH HHS · RF1 AG059421 · United States
Medical Research Council · MR/K026992/1 · United Kingdom
NHLBI NIH HHS · R01 HL105756 · United States
Medical Research Council · G0701120 · United Kingdom
NINDS NIH HHS · RF1 NS085002 · United States
NIA NIH HHS · P30 AG072972 · United States
Medical Research Council · MR/J006971/1 · United Kingdom
NINDS NIH HHS · R01 NS017950 · United States
Medical Research Council · MR/M013111/1 · United Kingdom
Medical Research Council · G1001245 · United Kingdom
NIA NIH HHS · P30 AG066546 · United States
NIA NIH HHS · U01 AG052409 · United States
External Links
PubMed source DOI: 10.1093/brain/awac290 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2