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

TitleGenome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.
Publication TypeJournal Article
Year of Publication2011
AuthorsFornage, M, Debette, S, Bis, JC, Schmidt, H, M Ikram, A, 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, J-C, 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, MMB, Mosley, TH, Schmidt, R, Longstreth, WT, DeCarli, C, Launer, LJ
JournalAnn Neurol
Volume69
Issue6
Pagination928-39
Date Published2011 Jun
ISSN1531-8249
KeywordsAged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger
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.

DOI10.1002/ana.22403
Alternate JournalAnn. Neurol.
PubMed ID21681796
PubMed Central IDPMC3122147
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
U01-HG004402 / HG / NHGRI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
R01 AG016495 / AG / NIA NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
R01 HL093029-01A1 / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
R01 HL087652-01 / HL / NHLBI NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
R01 AG040282 / AG / NIA NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
R01-HL087641 / HL / NHLBI NIH HHS / United States
R01 HL093029 / HL / NHLBI NIH HHS / United States
NS17950 / NS / NINDS NIH HHS / United States
R01-HL087652 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
P 20545 / / Austrian Science Fund FWF / Austria
AG08122 / AG / NIA NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
/ / Intramural NIH HHS / United States
R01 HL093029-02 / HL / NHLBI NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
M01RR00425 / RR / NCRR NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-55222 / HC / NHLBI NIH HHS / United States
R01-HL093029 / HL / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
AG031287 / AG / NIA NIH HHS / United States
M01 RR000425 / RR / NCRR NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
R01 HL087641-01 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
AG16495 / AG / NIA NIH HHS / United States
R01 AG033193-01 / AG / NIA NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
K23 AG038444 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R01 AG031287 / AG / NIA NIH HHS / United States