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

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

doi:10.1002/ana.22403

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

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

Research output: Contribution to journal › Article › Academic › peer-review

180 Citations (Scopus)

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 x 10(-9); p(replication) = 1.3 x 10(-7); p(combined) = 4.0 x 10(-15)). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 x 10(-9)), rs11869977 (p = 5.7 x 10(-9)), rs936393 (p = 6.8 x 10(-9)), rs3744017 (p = 7.3 x 10(-9)), and rs1055129 (p = 4.1 x 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

Original language	Undefined/Unknown
Pages (from-to)	928-939
Number of pages	12
Journal	Annals of Neurology
Volume	69
Issue number	6
DOIs	https://doi.org/10.1002/ana.22403
Publication status	Published - 2011

Research programs

EMC MM-01-25-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC NIHES-01-64-02
EMC NIHES-03-30-01
EMC NIHES-03-30-03

Access to Document

10.1002/ana.22403

http://hdl.handle.net/1765/26612

Cite this

Fornage, M., Debette, S., Bis, JC., Schmidt, H., Ikram, A., Dufouil, C., Sigurdsson, S., Lumley, T., DeStefano, AL., Fazekas, F., Vrooman, H., Shibata, DK., Maillard, P., Zijdenbos, A., Smith, AV., Gudnason, H., Boer, R., Cushman, M., Mazoyer, B., ... Launer, LJ. (2011). Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium. Annals of Neurology, 69(6), 928-939. https://doi.org/10.1002/ana.22403

@article{6323a574e21c4048a6fc6dfdd44f6d17,

title = "Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium",

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 x 10(-9); p(replication) = 1.3 x 10(-7); p(combined) = 4.0 x 10(-15)). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 x 10(-9)), rs11869977 (p = 5.7 x 10(-9)), rs936393 (p = 6.8 x 10(-9)), rs3744017 (p = 7.3 x 10(-9)), and rs1055129 (p = 4.1 x 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",

author = "M Fornage and S Debette and JC Bis and Hel{\'e}na Schmidt and Arfan Ikram and C Dufouil and S Sigurdsson and T Lumley and AL DeStefano and F Fazekas and Henri Vrooman and DK Shibata and P Maillard and A Zijdenbos and AV Smith and H Gudnason and Renske Boer and M Cushman and B Mazoyer and G Heiss and Meike Vernooij and C Enzinger and NL Glazer and A Beiser and DS Knopman and M Cavalieri and Wiro Niessen and TB Harris and K Petrovic and OL Lopez and Au, {R (Rhoda)} and JC Lambert and Bert Hofman and RF Gottesman and M Garcia and SR Heckbert and LD Atwood and DJ Catellier and Andr{\'e} Uitterlinden and Q Yang and NL Smith and T Aspelund and JR Romero and K Rice and KD Taylor and MA Nalls and JI Rotter and R Sharrett and Cornelia Duijn and P Amouyel and PA Wolf and V Gudnason and {van der Lugt}, Aad and E Boerwinkle and BM Psaty and S Seshadri and C Tzourio and Monique Breteler and TH Mosley and R Schmidt and WT Longstreth and C DeCarli and Launer, {LJ (Lenore)}",

year = "2011",

doi = "10.1002/ana.22403",

language = "Undefined/Unknown",

volume = "69",

pages = "928--939",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "6",

}

Fornage, M, Debette, S, Bis, JC, Schmidt, H, Ikram, A, Dufouil, C, Sigurdsson, S, Lumley, T, DeStefano, AL, Fazekas, F, Vrooman, H, Shibata, DK, Maillard, P, Zijdenbos, A, Smith, AV, Gudnason, H, Boer, R, Cushman, M, Mazoyer, B, Heiss, G, Vernooij, M, Enzinger, C, Glazer, NL, Beiser, A, Knopman, DS, Cavalieri, M, Niessen, W, Harris, TB, Petrovic, K, Lopez, OL, Au, R, Lambert, JC, Hofman, B, Gottesman, RF, Garcia, M, Heckbert, SR, Atwood, LD, Catellier, DJ, Uitterlinden, A, Yang, Q, Smith, NL, Aspelund, T, Romero, JR, Rice, K, Taylor, KD, Nalls, MA, Rotter, JI, Sharrett, R, Duijn, C, Amouyel, P, Wolf, PA, Gudnason, V, van der Lugt, A, Boerwinkle, E, Psaty, BM, Seshadri, S, Tzourio, C, Breteler, M, Mosley, TH, Schmidt, R, Longstreth, WT, DeCarli, C & Launer, LJ 2011, 'Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium', Annals of Neurology, vol. 69, no. 6, pp. 928-939. https://doi.org/10.1002/ana.22403

TY - JOUR

T1 - Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium

AU - Fornage, M

AU - Debette, S

AU - Bis, JC

AU - Schmidt, Heléna

AU - Ikram, Arfan

AU - Dufouil, C

AU - Sigurdsson, S

AU - Lumley, T

AU - DeStefano, AL

AU - Fazekas, F

AU - Vrooman, Henri

AU - Shibata, DK

AU - Maillard, P

AU - Zijdenbos, A

AU - Smith, AV

AU - Gudnason, H

AU - Boer, Renske

AU - Cushman, M

AU - Mazoyer, B

AU - Heiss, G

AU - Vernooij, Meike

AU - Enzinger, C

AU - Glazer, NL

AU - Beiser, A

AU - Knopman, DS

AU - Cavalieri, M

AU - Niessen, Wiro

AU - Harris, TB

AU - Petrovic, K

AU - Lopez, OL

AU - Au, R (Rhoda)

AU - Lambert, JC

AU - Hofman, Bert

AU - Gottesman, RF

AU - Garcia, M

AU - Heckbert, SR

AU - Atwood, LD

AU - Catellier, DJ

AU - Uitterlinden, André

AU - Yang, Q

AU - Smith, NL

AU - Aspelund, T

AU - Romero, JR

AU - Rice, K

AU - Taylor, KD

AU - Nalls, MA

AU - Rotter, JI

AU - Sharrett, R

AU - Duijn, Cornelia

AU - Amouyel, P

AU - Wolf, PA

AU - Gudnason, V

AU - van der Lugt, Aad

AU - Boerwinkle, E

AU - Psaty, BM

AU - Seshadri, S

AU - Tzourio, C

AU - Breteler, Monique

AU - Mosley, TH

AU - Schmidt, R

AU - Longstreth, WT

AU - DeCarli, C

AU - Launer, LJ (Lenore)

PY - 2011

Y1 - 2011

N2 - 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 x 10(-9); p(replication) = 1.3 x 10(-7); p(combined) = 4.0 x 10(-15)). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 x 10(-9)), rs11869977 (p = 5.7 x 10(-9)), rs936393 (p = 6.8 x 10(-9)), rs3744017 (p = 7.3 x 10(-9)), and rs1055129 (p = 4.1 x 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

AB - 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 x 10(-9); p(replication) = 1.3 x 10(-7); p(combined) = 4.0 x 10(-15)). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 x 10(-9)), rs11869977 (p = 5.7 x 10(-9)), rs936393 (p = 6.8 x 10(-9)), rs3744017 (p = 7.3 x 10(-9)), and rs1055129 (p = 4.1 x 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

U2 - 10.1002/ana.22403

DO - 10.1002/ana.22403

M3 - Article

C2 - 21681796

SN - 0364-5134

VL - 69

SP - 928

EP - 939

JO - Annals of Neurology

JF - Annals of Neurology

IS - 6

ER -