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)

1 UTHealth - The University of Texas Health Science Center at Houston
2 BUSM - Boston University School of Medicine
3 Cardiovascular Health Research Unit, University of Washington
4 Department of Medicine, University of Washington
5 Institute of Molecular Biology and Biochemistry, Medical University Graz
6 NCHA - Netherlands Consortium for Healthy Aging [Leiden, Netherlands]
7 Erasmus MC - Erasmus University Medical Center [Rotterdam]
8 UPMC - Université Pierre et Marie Curie - Paris 6
9 Icelandic Heart Association
10 Department of Biostatistics, University of Washington
11 BU - Boston University [Boston]
12 Department of Neurology
13 Department of Radiology, University of Washington
14 GIN - UMR 5296 - Groupe d'Imagerie Neurofonctionnelle
15 Biospective [Montréal]
16 Neurological Institute, McGill University
17 University of Vermont [Burlington]
18 UNC - University of North Carolina [Chapel Hill]
19 Mayo Clinic [Rochester]
20 UniFE - Università degli Studi di Ferrara = University of Ferrara
21 NIH - National Institutes of Health [Bethesda, MD, USA]
22 University of Pittsburgh School of Medicine
23 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
24 Johns Hopkins University School of Medicine [Baltimore]
25 Department of Epidemiology, University of Washington
26 Group Health Research Institute, Group Health Cooperative
27 Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development
28 University of Iceland [Reykjavik]
29 Cedars-Sinai Medical Center
30 Department of Health Services, University of Washington
31 UMMC - University of Mississippi Medical Center
32 Department of Neurology, University of Washington
33 UC Davis - University of California [Davis]

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.

Domaines: Neurosciences

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, 2011, 69, pp.928-939. ⟨10.1002/ana.22403⟩. ⟨hal-01154260⟩