Dataset Information

Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.

ABSTRACT: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

SUBMITTER: Fornage M

PROVIDER: S-EPMC3122147 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.

Fornage Myriam M Debette Stephanie S Bis Joshua C JC Schmidt Helena H Ikram M Arfan MA Dufouil Carole C Sigurdsson Sigurdur S Lumley Thomas T DeStefano Anita L AL Fazekas Franz F Vrooman Henri A HA Shibata Dean K DK Maillard Pauline P Zijdenbos Alex A Smith Albert V AV Gudnason Haukur H de Boer Renske R Cushman Mary M Mazoyer Bernard B Heiss Gerardo G Vernooij Meike W MW Enzinger Christian C Glazer Nicole L NL Beiser Alexa A Knopman David S DS Cavalieri Margherita M Niessen Wiro J WJ Harris Tamara B TB Petrovic Katja K Lopez Oscar L OL Au Rhoda R Lambert Jean-Charles JC Hofman Albert A Gottesman Rebecca F RF Garcia Melissa M Heckbert Susan R SR Atwood Larry D LD Catellier Diane J DJ Uitterlinden Andre G AG Yang Qiong Q Smith Nicholas L NL Aspelund Thor T Romero Jose R JR Rice Kenneth K Taylor Kent D KD Nalls Michael A MA Rotter Jerome I JI Sharrett Richey R van Duijn Cornelia M CM Amouyel Philippe P Wolf Philip A PA Gudnason Vilmundur V van der Lugt Aad A Boerwinkle Eric E Psaty Bruce M BM Seshadri Sudha S Tzourio Christophe C Breteler Monique M B MM Mosley Thomas H TH Schmidt Reinhold R Longstreth W T WT DeCarli Charles C Launer Lenore J LJ

Annals of neurology 20110601 6

<h4>Objective</h4>White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.<h4>Methods</h4>We performed a meta- ...[more]

PMID: 21681796

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Project description:Background and purposePrevious studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.MethodsUsing 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).ResultsThe most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.ConclusionsThis first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

Dataset Information

Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.

Publications

Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.

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