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

被引：19

作者：

Yang, Yunju ^{[1
]}

Knol, Maria J. ^{[2
]}

Wang, Ruiqi ^{[3
]}

Mishra, Aniket ^{[4
]}

Liu, Dan ^{[5
]}

Luciano, Michelle ^{[6
]}

Teumer, Alexander ^{[7
,8
,9
]}

Armstrong, Nicola ^{[10
]}

Bis, Joshua C. ^{[11
]}

Jhun, Min A. ^{[12
]}

Li, Shuo

Adams, Hieab H. H. ^{[2
,13
]}

Aziz, Nasir Ahmad ^{[5
,14
]}

Bastin, Mark E. ^{[15
]}

Bourgey, Mathieu ^{[16
,17
]}

Smith, Jennifer A. ^{[12
]}

Frenzel, Stefan ^{[18
]}

Gottesman, Rebecca F. ^{[19
]}

Hosten, Norbert ^{[20
]}

Hou, Lifang ^{[21
]}

Kardia, Sharon L. R. ^{[12
]}

Lohner, Valerie ^{[5
]}

Marquis, Pascale ^{[16
,17
]}

Maniega, Susana Munoz ^{[15
]}

Satizabal, Claudia L. ^{[22
,23
,24
,25
,26
]}

Sorond, Farzaneh A. ^{[27
]}

Valdes Hernandez, Maria C. ^{[15
]}

van Duijn, Cornelia M. ^{[2
,28
]}

Vernooij, Meike W. ^{[2
,13
]}

Wittfeld, Katharina ^{[18
,29
]}

Yang, Qiong ^{[3
,25
]}

Zhao, Wei ^{[12
]}

Boerwinkle, Eric ^{[30
,31
]}

Levy, Daniel ^{[25
,32
]}

Deary, Ian J.

Jiang, Jiyang ^{[33
]}

Mather, Karen A. ^{[33
,34
]}

Mosley, Thomas H. ^{[35
]}

Psaty, Bruce M. ^{[11
,36
]}

Sachdev, Perminder S. ^{[33
,37
,38
]}

Smith, Jennifer A. ^{[12
]}

Sotoodehnia, Nona ^{[11
]}

DeCarli, Charles S. ^{[39
,40
]}

Breteler, Monique M. B. ^{[5
,41
]}

Ikram, M. Arfan ^{[2
]}

Grabe, Hans J. ^{[18
,29
]}

Wardlaw, Joanna ^{[15
]}

Longstreth, W. T. ^{[36
,42
]}

Launer, Lenore J.

Seshadri, Sudha ^{[22
,23
,24
,25
,26
]}

机构：

[1] Univ Texas Hlth Sci Houston, Brown Fdn, McGovern Med Sch, Inst Mol Med, 1825 Pressler St,Suite 530F, Houston, TX 77030 USA

[2] Univ Med Ctr, Dept Epidemiol, Erasmus MC, NL-3015 GD Rotterdam, Netherlands

[3] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA

[4] Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, Team VINTAGE,UMR 1219, F-33000 Bordeaux, France

[5] German Ctr Neurodegenerat Dis DZNE, Populat Hlth Sci, D-53127 Bonn, Germany

[6] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland

[7] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany

[8] German Ctr Cardiovasc Res DZHK, Partner Site Greifswald, D-17475 Greifswald, Germany

[9] Med Univ Bialystok, Dept Populat Med & Lifestyle Dis Prevent, PL-15269 Bialystok, Poland

[10] Curtin Univ, Math & Stat, Perth, WA 6845, Australia

[11] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[12] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48104 USA

[13] Univ Med Ctr, Dept Radiol & Nucl Med, Erasmus MC, NL-3015 GD Rotterdam, Netherlands

[14] Univ Bonn, Fac Med, Dept Neurol, D-53127 Bonn, Germany

[15] Univ Edinburgh, Ctr Clin Brain Sci, Dept Neuroimaging Sci, Edinburgh EH8 9AB, Midlothian, Scotland

[16] McGill Univ, Canadian Ctr Computat Genom, Montreal, PQ H3A 0G1, Canada

[17] McGill Univ, Genome Ctr, Dept Human Genet, Montreal, PQ H3A 0G1, Canada

[18] Univ Med Greifswald, Dept Psychiat & Psychotherapy, D-17475 Greifswald, Germany

[19] NINDS, Stroke Branch, Bethesda, MD 20814 USA

[20] Univ Med Greifswald, Dept Radiol & Neuroradiol, D-17475 Greifswald, Germany

[21] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA

[22] UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX 78229 USA

[23] UT Hlth San Antonio, Dept Populat Hlth Sci, San Antonio, TX 78229 USA

[24] Framingham Heart Dis Epidemiol Study, Framingham, MA 01701 USA

[25] Boston Univ, Dept Neurol, Sch Med, Boston, MA 02115 USA

[26] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA

[27] Univ Oxford, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England

[28] German Ctr Neurodegenerat Dis DZNE, Site Rostock Greifswald, D-17475 Rostock, Germany

[29] Univ Texas Hlth Sci Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA

[30] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[31] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20814 USA

[32] Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia

[33] Neurosci Res Australia, Sydney, NSW 2031, Australia

[34] Univ Mississippi, Memory Impairment Neurodegenerat Dementia MIND Re, Jackson, MS 39216 USA

[35] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA

[36] Univ New South Wales, Prince Wales Hosp, Neuropsychiat Inst, Randwick, NSW 2031, Australia

[37] Univ Calif Davis, Dept Neurol, Sacramento, CA 95816 USA

[38] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95816 USA

[39] Univ Bonn, Inst Med Biometry Informat & Epidemiol IMBIE, Fac Med, D-53127 Bonn, Germany

[40] Univ Washington, Dept Neurol, Seattle, WA 98104 USA

[41] NIA, Intramural Res Program, NIH, Bethesda, MD 20814 USA

[42] CHU Bordeaux, Dept Neurol, F-33000 Bordeaux, France

来源：

BRAIN | 2023年 / 146卷 / 02期

关键词：

epigenome-wide association study; white matter hyperintensities; cerebral small vessel disease; integrative cross-omics analysis; blood-brain barrier dysfunction; SMALL-VESSEL DISEASE; GENOME-WIDE ASSOCIATION; ASYMMETRIC DIMETHYLARGININE; N-ACETYLASPARTYLGLUTAMATE; SEVERE HYPOMYELINATION; GENE-EXPRESSION; BLOOD; DESIGN; MARKERS; ARGININE;

D O I：

10.1093/brain/awac290

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Yang et al. investigate the association between epigenetic changes and white matter hyperintensities-markers of cerebral small vessel disease-in 9732 adults. Integrative cross-omics analyses implicate blood-brain barrier dysfunction and the immune response in WMH burden, and suggest antihyperlipidemic agents as a potential treatment. 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 similar to 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 x 10(-8)), was associated with F2 expression in blood (P = 6.4 x 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.

引用

页码：492 / 506

页数：15

共 143 条

[1] The GTEx Consortium atlas of genetic regulatory effects across human tissues [J].

Aguet, Francois ;

Barbeira, Alvaro N. ;

Bonazzola, Rodrigo ;

Brown, Andrew ;

Castel, Stephane E. ;

Jo, Brian ;

Kasela, Silva ;

Kim-Hellmuth, Sarah ;

Liang, Yanyu ;

Parsana, Princy ;

Flynn, Elise ;

Fresard, Laure ;

Gamazon, Eric R. ;

Hamel, Andrew R. ;

He, Yuan ;

Hormozdiari, Farhad ;

Mohammadi, Pejman ;

Munoz-Aguirre, Manuel ;

Ardlie, Kristin G. ;

Battle, Alexis ;

Bonazzola, Rodrigo ;

Brown, Christopher D. ;

Cox, Nancy ;

Dermitzakis, Emmanouil T. ;

Engelhardt, Barbara E. ;

Garrido-Martin, Diego ;

Gay, Nicole R. ;

Getz, Gad ;

Guigo, Roderic ;

Hamel, Andrew R. ;

Handsaker, Robert E. ;

He, Yuan ;

Hoffman, Paul J. ;

Hormozdiari, Farhad ;

Im, Hae Kyung ;

Jo, Brian ;

Kasela, Silva ;

Kashin, Seva ;

Kim-Hellmuth, Sarah ;

Kwong, Alan ;

Lappalainen, Tuuli ;

Li, Xiao ;

Liang, Yanyu ;

MacArthur, Daniel G. ;

Mohammadi, Pejman ;

Montgomery, Stephen B. ;

Munoz-Aguirre, Manuel ;

Rouhana, John M. ;

Hormozdiari, Farhad ;

Im, Hae Kyung .

SCIENCE, 2020, 369 (6509) :1318-1330

[2] The role of extracellular matrix alterations in mediating astrocyte damage and pericyte dysfunction in Alzheimer's disease: A comprehensive review [J].

Anwar, Mai M. ;

Ozkan, Esra ;

Gursoy-Ozdemir, Yasemin .

EUROPEAN JOURNAL OF NEUROSCIENCE, 2022, 56 (09) :5453-5475

[3] Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities [J].

Armstrong, Nicola J. ;

Mather, Karen A. ;

Sargurupremraj, Muralidharan ;

Knol, Maria J. ;

Malik, Rainer ;

Satizabal, Claudia L. ;

Yanek, Lisa R. ;

Wen, Wei ;

Gudnason, Vilmundur G. ;

Dueker, Nicole D. ;

Elliott, Lloyd T. ;

Hofer, Edith ;

Bis, Joshua ;

Jahanshad, Neda ;

Li, Shuo ;

Logue, Mark A. ;

Luciano, Michelle ;

Scholz, Markus ;

Smith, Albert V. ;

Trompet, Stella ;

Vojinovic, Dina ;

Xia, Rui ;

Alfaro-Almagro, Fidel ;

Ames, David ;

Amin, Najaf ;

Amouyel, Philippe ;

Beiser, Alexa S. ;

Brodaty, Henry ;

Deary, Ian J. ;

Fennema-Notestine, Christine ;

Gampawar, Piyush G. ;

Gottesman, Rebecca ;

Griffanti, Ludovica ;

Jack, Clifford R., Jr. ;

Jenkinson, Mark ;

Jiang, Jiyang ;

Kral, Brian G. ;

Kwok, John B. ;

Lampe, Leonie ;

Liewald, David C. M. ;

Maillard, Pauline ;

Marchini, Jonathan ;

Bastin, Mark E. ;

Mazoyer, Bernard ;

Pirpamer, Lukas ;

Rafael Romero, Jose ;

Roshchupkin, Gennady V. ;

Schofield, Peter R. ;

Schroeter, Matthias L. ;

Stott, David J. .

STROKE, 2020, 51 (07) :2111-2121

[4] Mergeomics: a web server for identifying pathological pathways, networks, and key regulators via multidimensional data integration [J].

Arneson, Douglas ;

Bhattacharya, Anindya ;

Shu, Le ;

Makinen, Ville-Petteri ;

Yang, Xia .

BMC GENOMICS, 2016, 17

[5] Gene Ontology: tool for the unification of biology [J].

Ashburner, M ;

Ball, CA ;

Blake, JA ;

Botstein, D ;

Butler, H ;

Cherry, JM ;

Davis, AP ;

Dolinski, K ;

Dwight, SS ;

Eppig, JT ;

Harris, MA ;

Hill, DP ;

Issel-Tarver, L ;

Kasarskis, A ;

Lewis, S ;

Matese, JC ;

Richardson, JE ;

Ringwald, M ;

Rubin, GM ;

Sherlock, G .

NATURE GENETICS, 2000, 25 (01) :25-29

[6] Genetic variation in white matter hyperintensity volume in the Framingham study [J].

Atwood, LD ;

Wolf, PA ;

Heard-Costa, NL ;

Massaro, JM ;

Beiser, A ;

D'Agostino, RB ;

DeCarli, C .

STROKE, 2004, 35 (07) :1609-1613

[7] 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 [J].

Bailey, E. L. ;

Wardlaw, J. M. ;

Graham, D. ;

Dominiczak, A. F. ;

Sudlow, C. L. M. ;

Smith, C. .

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 2011, 37 (07) :711-726

[8]

Battram Thomas, 2022, Wellcome Open Res, V7, P41, DOI 10.12688/wellcomeopenres.17598.1

[9]

BBMRI Stakeholder's Forum, BBMRI STEP CLOS STAK

[10]

Belinky Frida, 2015, Database (Oxford), V2015, DOI 10.1093/database/bav006

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