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Genome‐wide association studies of cerebral white matter lesion burden
Author(s) -
Fornage Myriam,
Debette Stephanie,
Bis Joshua C.,
Schmidt Helena,
Ikram M. Arfan,
Dufouil Carole,
Sigurdsson Sigurdur,
Lumley Thomas,
DeStefano Anita L.,
Fazekas Franz,
Vrooman Henri A.,
Shibata Dean K.,
Maillard Pauline,
Zijdenbos Alex,
Smith Albert V.,
Gudnason Haukur,
de Boer Renske,
Cushman Mary,
Mazoyer Bernard,
Heiss Gerardo,
Vernooij Meike W.,
Enzinger Christian,
Glazer Nicole L.,
Beiser Alexa,
Knopman David S.,
Cavalieri Margherita,
Niessen Wiro J.,
Harris Tamara B.,
Petrovic Katja,
Lopez Oscar L.,
Au Rhoda,
Lambert JeanCharles,
Hofman Albert,
Gottesman Rebecca F.,
Garcia Melissa,
Heckbert Susan R.,
Atwood Larry D.,
Catellier Diane J.,
Uitterlinden Andre G.,
Yang Qiong,
Smith Nicholas L.,
Aspelund Thor,
Romero Jose R.,
Rice Kenneth,
Taylor Kent D.,
Nalls Michael A.,
Rotter Jerome I.,
Sharrett Richey,
van Duijn Cornelia M.,
Amouyel Philippe,
Wolf Philip A.,
Gudnason Vilmundur,
van der Lugt Aad,
Boerwinkle Eric,
Psaty Bruce M.,
Seshadri Sudha,
Tzourio Christophe,
Breteler Monique M. B.,
Mosley Thomas H.,
Schmidt Reinhold,
Longstreth W. T.,
DeCarli Charles,
Launer Lenore J.
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22403
Subject(s) - genome wide association study , single nucleotide polymorphism , hyperintensity , locus (genetics) , genetic association , dementia , white matter , snp , medicine , allele , genetics , oncology , biology , magnetic resonance imaging , disease , gene , genotype , radiology
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. Ann Neurol 2011;69:928–939