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Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium

M Fornage 1 S Debette 2 Jc Bis 3, 4 H Schmidt 5 Ma Ikram 6, 7 C Dufouil 8 S Sigurdsson 9 T Lumley 10 Al Destefano 2, 11 F Fazekas 12 Ha Vrooman 7 Dk Shibata 13 Pauline Maillard 14 A Zijdenbos 15, 16 Av Smith 9 H Gudnason 9 R de Boer 7 M Cushman 17 Bernard Mazoyer 14 G Heiss 18 Mw Vernooij 7 C Enzinger 12 Nl Glazer 3, 4 A Beiser 2, 11 Ds Knopman 19 M Cavalieri 12, 20 Wj Niessen 7 Tb Harris 21 K Petrovic 12 Ol Lopez 22 R Au 2 Jc Lambert 23 A Hofman 7, 6 Rf Gottesman 24 M Garcia 21 Sr Heckbert 25, 26 Ld Atwood 2 Dj Catellier 18 Ag Uitterlinden 7, 6 Q Yang 11 Nl Smith 25, 27 T Aspelund 9, 28 Jr Romero 2 K Rice 10 Kd Taylor 29 Ma Nalls 21 Ji Rotter 29 R Sharrett 24 Cm van Duijn 7, 6 P Amouyel 23 Pa Wolf 2 V Gudnason 9, 28 A van der Lugt 7 E Boerwinkle 1 Bm Psaty 3, 4, 25, 26, 30 S Seshadri 2 C Tzourio 8 Mm Breteler 7, 6 Th Mosley 31 R Schmidt 12 Wt Longstreth 3, 4, 25, 32 C Decarli 33 Lj Launer 20
Abstract : OBJECTIVE: 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. METHODS: 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. RESULTS: 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). INTERPRETATION: 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.
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M Fornage, S Debette, Jc Bis, H Schmidt, Ma Ikram, et al.. Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium. Annals of Neurology, Wiley, 2011, 69, pp.928-939. ⟨10.1002/ana.22403⟩. ⟨hal-01154260⟩

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