Dataset Information

Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

ABSTRACT: BACKGROUND:The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. METHODS AND RESULTS:We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). CONCLUSIONS:We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

SUBMITTER: Verhaaren BF

PROVIDER: S-EPMC4427240 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

Verhaaren Benjamin F J BF Debette Stéphanie S Bis Joshua C JC Smith Jennifer A JA Ikram M Kamran MK Adams Hieab H HH Beecham Ashley H AH Rajan Kumar B KB Lopez Lorna M LM Barral Sandra S van Buchem Mark A MA van der Grond Jeroen J Smith Albert V AV Hegenscheid Katrin K Aggarwal Neelum T NT de Andrade Mariza M Atkinson Elizabeth J EJ Beekman Marian M Beiser Alexa S AS Blanton Susan H SH Boerwinkle Eric E Brickman Adam M AM Bryan R Nick RN Chauhan Ganesh G Chen Christopher P L H CP Chouraki Vincent V de Craen Anton J M AJ Crivello Fabrice F Deary Ian J IJ Deelen Joris J De Jager Philip L PL Dufouil Carole C Elkind Mitchell S V MS Evans Denis A DA Freudenberger Paul P Gottesman Rebecca F RF Guðnason Vilmundur V Habes Mohamad M Heckbert Susan R SR Heiss Gerardo G Hilal Saima S Hofer Edith E Hofman Albert A Ibrahim-Verbaas Carla A CA Knopman David S DS Lewis Cora E CE Liao Jiemin J Liewald David C M DC Luciano Michelle M van der Lugt Aad A Martinez Oliver O OO Mayeux Richard R Mazoyer Bernard B Nalls Mike M Nauck Matthias M Niessen Wiro J WJ Oostra Ben A BA Psaty Bruce M BM Rice Kenneth M KM Rotter Jerome I JI von Sarnowski Bettina B Schmidt Helena H Schreiner Pamela J PJ Schuur Maaike M Sidney Stephen S SS Sigurdsson Sigurdur S Slagboom P Eline PE Stott David J M DJ van Swieten John C JC Teumer Alexander A Töglhofer Anna Maria AM Traylor Matthew M Trompet Stella S Turner Stephen T ST Tzourio Christophe C Uh Hae-Won HW Uitterlinden André G AG Vernooij Meike W MW Wang Jing J JJ Wong Tien Y TY Wardlaw Joanna M JM Windham B Gwen BG Wittfeld Katharina K Wolf Christiane C Wright Clinton B CB Yang Qiong Q Zhao Wei W Zijdenbos Alex A Jukema J Wouter JW Sacco Ralph L RL Kardia Sharon L R SL Amouyel Philippe P Mosley Thomas H TH Longstreth W T WT DeCarli Charles C CC van Duijn Cornelia M CM Schmidt Reinhold R Launer Lenore J LJ Grabe Hans J HJ Seshadri Sudha S SS Ikram M Arfan MA Fornage Myriam M

Circulation. Cardiovascular genetics 20150207 2

<h4>Background</h4>The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.<h4>Methods and results</h4>We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were fre ...[more]

PMID: 25663218

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Project description: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.

Project description:BACKGROUND:Cerebral white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) are part of the spectrum of brain vascular injury accompanying aging and are associated with a substantial risk of stroke and dementia. We investigated the association of cerebral WMH burden on MRI with a DNA methylation-based biomarker of aging, termed DNA methylation age acceleration, which represents the deviation of the DNA methylation-predicted age from the chronologic age. RESULTS:In this cross-sectional observational study of 713 African-American participants of the Atherosclerosis Risk in Communities study, aged 51-73 years, estimates of predicted age were obtained based on two algorithms (Hannum et al. and Horvath) from DNA methylation measured using the Illumina HM450 array on genomic DNA extracted from blood. Age acceleration, calculated as the residual values from the regression of each of the predicted age measures onto the chronologic age, was significantly associated with WMH burden after accounting for chronologic age and sex, body mass index, systolic blood pressure, hypertension, diabetes, current smoking, and blood cell composition, and results were similar for either Hannum et al.- or Horvath-derived estimates (P?=?0.016 and 0.026). An age acceleration increase by 1 year was associated with an increase of WMH burden by ~1 grade. To shed light on possible biological mechanisms underlying this association, we conducted a genome-wide association study of age acceleration and identified four loci harboring genes implicated in hemostasis, cell proliferation, protein degradation, and histone methylation. However, none of these loci were associated with WMH burden. CONCLUSIONS:In this population-based study of middle-aged to older African-American adults, we report an association between accelerated epigenetic aging and increased WMH burden, independent of known risk factors, including chronologic age. Additional studies are needed to clarify whether DNA methylation age reflects biological mechanisms implicated in the aging of the cerebral white matter.

Project description:Background: White matter hyperintensities of presumed vascular origin (WMH) are a common finding in elderly people and a growing social malady in the aging western societies. As a manifestation of cerebral small vessel disease, WMH are considered to be a vascular contributor to various sequelae such as cognitive decline, dementia, depression, stroke as well as gait and balance problems. While pathophysiology and therapeutical options remain unclear, large-scale studies have improved the understanding of WMH, particularly by quantitative assessment of WMH. In this review, we aimed to provide an overview of the characteristics, research subjects and segmentation techniques of these studies. Methods: We performed a systematic review according to the PRISMA statement. One thousand one hundred and ninety-six potentially relevant articles were identified via PubMed search. Six further articles classified as relevant were added manually. After applying a catalog of exclusion criteria, remaining articles were read full-text and the following information was extracted into a standardized form: year of publication, sample size, mean age of subjects in the study, the cohort included, and segmentation details like the definition of WMH, the segmentation method, reference to methods papers as well as validation measurements. Results: Our search resulted in the inclusion and full-text review of 137 articles. One hundred and thirty-four of them belonged to 37 prospective cohort studies. Median sample size was 1,030 with no increase over the covered years. Eighty studies investigated in the association of WMH and risk factors. Most of them focussed on arterial hypertension, diabetes mellitus type II and Apo E genotype and inflammatory markers. Sixty-three studies analyzed the association of WMH and secondary conditions like cognitive decline, mood disorder and brain atrophy. Studies applied various methods based on manual (3), semi-automated (57), and automated segmentation techniques (75). Only 18% of the articles referred to an explicit definition of WMH. Discussion: The review yielded a large number of studies engaged in WMH research. A remarkable variety of segmentation techniques was applied, and only a minority referred to a clear definition of WMH. Most addressed topics were risk factors and secondary clinical conditions. In conclusion, WMH research is a vivid field with a need for further standardization regarding definitions and used methods.

Dataset Information

Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

Publications

Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

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