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

doi:10.1002/ana.22403

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 HeissMeike 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

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

137 Scopus citations

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.

Original language	English (US)
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
State	Published - Jun 2011
Externally published	Yes

ASJC Scopus subject areas

Neurology
Clinical Neurology

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Fornage, M., Debette, S., Bis, J. C., Schmidt, H., Ikram, M. A., Dufouil, C., Sigurdsson, S., Lumley, T., Destefano, A. L., Fazekas, F., Vrooman, H. A., Shibata, D. K., Maillard, P., Zijdenbos, A., Smith, A. V., Gudnason, H., De Boer, R., Cushman, M., Mazoyer, B., ... Launer, L. J. (2011). Genome-wide association studies of cerebral white matter lesion burden. Annals of neurology, 69(6), 928-939. https://doi.org/10.1002/ana.22403

Fornage, M, 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, MMB, Mosley, TH, Schmidt, R, Longstreth, WT, Decarli, C & Launer, LJ 2011, 'Genome-wide association studies of cerebral white matter lesion burden', Annals of neurology, vol. 69, no. 6, pp. 928-939. https://doi.org/10.1002/ana.22403

@article{90ec026d8010470c8dc6fcffd6132821,

title = "Genome-wide association studies of cerebral white matter lesion burden",

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; preplication = 1.3 × 10-7; pcombined = 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.",

author = "Myriam Fornage and Stephanie Debette and Bis, {Joshua C.} and Helena Schmidt and Ikram, {M. Arfan} and Carole Dufouil and Sigurdur Sigurdsson and Thomas Lumley and Destefano, {Anita L.} and Franz Fazekas and Vrooman, {Henri A.} and Shibata, {Dean K.} and Pauline Maillard and Alex Zijdenbos and Smith, {Albert V.} and Haukur Gudnason and {De Boer}, Renske and Mary Cushman and Bernard Mazoyer and Gerardo Heiss and Vernooij, {Meike W.} and Christian Enzinger and Glazer, {Nicole L.} and Alexa Beiser and Knopman, {David S.} and Margherita Cavalieri and Niessen, {Wiro J.} and Harris, {Tamara B.} and Katja Petrovic and Lopez, {Oscar L.} and Rhoda Au and Lambert, {Jean Charles} and Albert Hofman and Gottesman, {Rebecca F.} and Melissa Garcia and Heckbert, {Susan R.} and Atwood, {Larry D.} and Catellier, {Diane J.} and Uitterlinden, {Andre G.} and Qiong Yang and Smith, {Nicholas L.} and Thor Aspelund and Romero, {Jose R.} and Kenneth Rice and Taylor, {Kent D.} and Nalls, {Michael A.} and Rotter, {Jerome I.} and Richey Sharrett and {Van Duijn}, {Cornelia M.} and Philippe Amouyel and Wolf, {Philip A.} and Vilmundur Gudnason and {Van Der Lugt}, Aad and Eric Boerwinkle and Psaty, {Bruce M.} and Sudha Seshadri and Christophe Tzourio and Breteler, {Monique M.B.} and Mosley, {Thomas H.} and Reinhold Schmidt and Longstreth, {W. T.} and Charles Decarli and Launer, {Lenore J.}",

year = "2011",

month = jun,

doi = "10.1002/ana.22403",

language = "English (US)",

volume = "69",

pages = "928--939",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

number = "6",

}

TY - JOUR

T1 - Genome-wide association studies of cerebral white matter lesion burden

AU - Fornage, Myriam

AU - Debette, Stephanie

AU - Bis, Joshua C.

AU - Schmidt, Helena

AU - Ikram, M. Arfan

AU - Dufouil, Carole

AU - Sigurdsson, Sigurdur

AU - Lumley, Thomas

AU - Destefano, Anita L.

AU - Fazekas, Franz

AU - Vrooman, Henri A.

AU - Shibata, Dean K.

AU - Maillard, Pauline

AU - Zijdenbos, Alex

AU - Smith, Albert V.

AU - Gudnason, Haukur

AU - De Boer, Renske

AU - Cushman, Mary

AU - Mazoyer, Bernard

AU - Heiss, Gerardo

AU - Vernooij, Meike W.

AU - Enzinger, Christian

AU - Glazer, Nicole L.

AU - Beiser, Alexa

AU - Knopman, David S.

AU - Cavalieri, Margherita

AU - Niessen, Wiro J.

AU - Harris, Tamara B.

AU - Petrovic, Katja

AU - Lopez, Oscar L.

AU - Au, Rhoda

AU - Lambert, Jean Charles

AU - Hofman, Albert

AU - Gottesman, Rebecca F.

AU - Garcia, Melissa

AU - Heckbert, Susan R.

AU - Atwood, Larry D.

AU - Catellier, Diane J.

AU - Uitterlinden, Andre G.

AU - Yang, Qiong

AU - Smith, Nicholas L.

AU - Aspelund, Thor

AU - Romero, Jose R.

AU - Rice, Kenneth

AU - Taylor, Kent D.

AU - Nalls, Michael A.

AU - Rotter, Jerome I.

AU - Sharrett, Richey

AU - Van Duijn, Cornelia M.

AU - Amouyel, Philippe

AU - Wolf, Philip A.

AU - Gudnason, Vilmundur

AU - Van Der Lugt, Aad

AU - Boerwinkle, Eric

AU - Psaty, Bruce M.

AU - Seshadri, Sudha

AU - Tzourio, Christophe

AU - Breteler, Monique M.B.

AU - Mosley, Thomas H.

AU - Schmidt, Reinhold

AU - Longstreth, W. T.

AU - Decarli, Charles

AU - Launer, Lenore J.

PY - 2011/6

Y1 - 2011/6

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 × 10-9; preplication = 1.3 × 10-7; pcombined = 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.

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 × 10-9; preplication = 1.3 × 10-7; pcombined = 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.

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U2 - 10.1002/ana.22403

DO - 10.1002/ana.22403

M3 - Article

C2 - 21681796

AN - SCOPUS:79959397958

SN - 0364-5134

VL - 69

SP - 928

EP - 939

JO - Annals of neurology

JF - Annals of neurology

IS - 6

ER -

Genome-wide association studies of cerebral white matter lesion burden

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