Genome-wide association studies of cerebral white matter lesion burden

Myriam Fornage, Stephanie Debette, Joshua C. Bis, Helena Schmidt, M. Arfan Ikram, Carole Dufouil, Sigurdur Sigurdsson, Thomas Lumley, Anita L. DeStefano, Franz Fazekas, Henri A. Vrooman, Dean K. Shibata, Pauline Maillard, Alex Zijdenbos, Albert V. Smith, Haukur Gudnason, Renske de Boer, Mary Cushman, Bernard Mazoyer, Gerardo Heiss, Meike W. Vernooij, Christian Enzinger, Nicole L. Glazer, Alexa Beiser, David S. Knopman, Margherita Cavalieri, Wiro J. Niessen, Tamara B. Harris, Katja Petrovic, Oscar L. Lopez, Rhoda Au, Jean-Charles Lambert, Albert Hofman, Rebecca F. Gottesman, Melissa Garcia, Susan R. Heckbert, Larry D. Atwood, Diane J. Catellier, Andre G. Uitterlinden, Qiong Yang, Nicholas L. Smith, Thor Aspelund, Jose R. Romero, Kenneth Rice, Kent D. Taylor, Michael A. Nalls, Jerome I. Rotter, Richey Sharrett, Cornelia M. van Duijn, Philippe Amouyel, Philip A. Wolf, Vilmundur Gudnason, Aad van der Lugt, Eric Boerwinkle, Bruce M. Psaty, Sudha Seshadri, Christophe Tzourio, Monique M. B. Breteler, Thomas H. Mosley, Reinhold Schmidt, W. T. Longstreth, Charles DeCarli, Lenore J. Launer
Ann Neurol.. 2011-06-01; 69(6): 928-939
DOI: 10.1002/ana.22403

Lire sur PubMed

1. Ann Neurol. 2011 Jun;69(6):928-39. doi: 10.1002/ana.22403.

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

Fornage M(1), Debette S, Bis JC, Schmidt H, Ikram MA, Dufouil C, Sigurdsson S,
Lumley T, DeStefano AL, Fazekas F, Vrooman HA, Shibata DK, Maillard P, Zijdenbos
A, Smith AV, Gudnason H, de Boer R, Cushman M, Mazoyer B, Heiss G, Vernooij MW,
Enzinger C, Glazer NL, Beiser A, Knopman DS, Cavalieri M, Niessen WJ, Harris TB,
Petrovic K, Lopez OL, Au R, Lambert JC, Hofman A, Gottesman RF, Garcia M,
Heckbert SR, Atwood LD, Catellier DJ, Uitterlinden AG, Yang Q, Smith NL, Aspelund
T, Romero JR, Rice K, Taylor KD, Nalls MA, Rotter JI, Sharrett R, van Duijn CM,
Amouyel P, Wolf PA, Gudnason V, van der Lugt A, Boerwinkle E, Psaty BM, Seshadri
S, Tzourio C, Breteler MM, Mosley TH, Schmidt R, Longstreth WT, DeCarli C, Launer

Author information:
(1)Brown Foundation Institute of Molecular Medicine, Division of Epidemiology,
School of Public Health, University of Texas Health Science Center at Houston,
Houston, TX, USA.

Comment in
Ann Neurol. 2011 Jun;69(6):907-8.

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.

Copyright © 2011 American Neurological Association.

DOI: 10.1002/ana.22403
PMCID: PMC3122147
PMID: 21681796 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus