Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium

S Debette; JC Bis; M Fornage; Heléna Schmidt; Arfan Ikram; S Sigurdsson; G Heiss; Maksim Struchalin; AV Smith; Aad van der Lugt; C DeCarli; T Lumley; DS Knopman; C Enzinger; G Eiriksdottir; Peter Koudstaal; AL DeStefano; BM Psaty; C Dufouil; DJ Catellier; F Fazekas; T Aspelund; YS Aulchenko; A Beiser; JI Rotter; C Tzourio; DK Shibata; M Tscherner; TB Harris; Fernando Rivadeneira; LD Atwood; K Rice; RF Gottesman; MA van Buchem; André Uitterlinden; M Kelly-Hayes; M Cushman; YC Zhu; E Boerwinkle; V Gudnason; Bert Hofman; JR Romero; O Lopez; Cornelia Duijn; R (Rhoda) Au; SR Heckbert; PA Wolf; TH Mosley; S Seshadri; Monique Breteler; R Schmidt; LJ (Lenore) Launer; WT Longstreth

doi:10.1161/STROKEAHA.109.569194

Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium

S Debette, JC Bis, M Fornage, Heléna Schmidt, Arfan Ikram, S Sigurdsson, G Heiss, Maksim Struchalin, AV Smith, Aad van der Lugt, C DeCarli, T Lumley, DS Knopman, C Enzinger, G Eiriksdottir, Peter Koudstaal, AL DeStefano, BM Psaty, C Dufouil, DJ CatellierF Fazekas, T Aspelund, YS Aulchenko, A Beiser, JI Rotter, C Tzourio, DK Shibata, M Tscherner, TB Harris, Fernando Rivadeneira, LD Atwood, K Rice, RF Gottesman, MA van Buchem, André Uitterlinden, M Kelly-Hayes, M Cushman, YC Zhu, E Boerwinkle, V Gudnason, Bert Hofman, JR Romero, O Lopez, Cornelia Duijn, R (Rhoda) Au, SR Heckbert, PA Wolf, TH Mosley, S Seshadri, Monique Breteler, R Schmidt, LJ (Lenore) Launer, WT Longstreth

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

82 Citations (Scopus)

Abstract

Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >= 1 MRI infarct). Results-The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P = 4.64 x 10(-7)). Highly suggestive associations (P < 1.0 x 10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2) > 0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions-This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed. (Stroke. 2010; 41: 210-217.)

Original language	Undefined/Unknown
Pages (from-to)	210-217
Number of pages	8
Journal	Stroke
Volume	41
Issue number	2
DOIs	https://doi.org/10.1161/STROKEAHA.109.569194
Publication status	Published - 2010

Research programs

EMC COEUR-09
EMC MM-01-39-02
EMC NIHES-01-64-01
EMC NIHES-01-64-02
EMC NIHES-03-30-01

Access to Document

10.1161/STROKEAHA.109.569194

http://hdl.handle.net/1765/19294

Cite this

Debette, S., Bis, JC., Fornage, M., Schmidt, H., Ikram, A., Sigurdsson, S., Heiss, G., Struchalin, M., Smith, AV., van der Lugt, A., DeCarli, C., Lumley, T., Knopman, DS., Enzinger, C., Eiriksdottir, G., Koudstaal, P., DeStefano, AL., Psaty, BM., Dufouil, C., ... Longstreth, WT. (2010). Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium. Stroke, 41(2), 210-217. https://doi.org/10.1161/STROKEAHA.109.569194

@article{2f4e1319a2a4405aa1117e6be7e6977e,

title = "Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium",

abstract = "Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >= 1 MRI infarct). Results-The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P = 4.64 x 10(-7)). Highly suggestive associations (P < 1.0 x 10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2) > 0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions-This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed. (Stroke. 2010; 41: 210-217.)",

author = "S Debette and JC Bis and M Fornage and Hel{\'e}na Schmidt and Arfan Ikram and S Sigurdsson and G Heiss and Maksim Struchalin and AV Smith and {van der Lugt}, Aad and C DeCarli and T Lumley and DS Knopman and C Enzinger and G Eiriksdottir and Peter Koudstaal and AL DeStefano and BM Psaty and C Dufouil and DJ Catellier and F Fazekas and T Aspelund and YS Aulchenko and A Beiser and JI Rotter and C Tzourio and DK Shibata and M Tscherner and TB Harris and Fernando Rivadeneira and LD Atwood and K Rice and RF Gottesman and {van Buchem}, MA and Andr{\'e} Uitterlinden and M Kelly-Hayes and M Cushman and YC Zhu and E Boerwinkle and V Gudnason and Bert Hofman and JR Romero and O Lopez and Cornelia Duijn and Au, {R (Rhoda)} and SR Heckbert and PA Wolf and TH Mosley and S Seshadri and Monique Breteler and R Schmidt and Launer, {LJ (Lenore)} and WT Longstreth",

year = "2010",

doi = "10.1161/STROKEAHA.109.569194",

language = "Undefined/Unknown",

volume = "41",

pages = "210--217",

journal = "Stroke",

issn = "0039-2499",

publisher = "Wolters Kluwer Health",

number = "2",

}

Debette, S, Bis, JC, Fornage, M, Schmidt, H, Ikram, A, Sigurdsson, S, Heiss, G, Struchalin, M, Smith, AV, van der Lugt, A, DeCarli, C, Lumley, T, Knopman, DS, Enzinger, C, Eiriksdottir, G, Koudstaal, P, DeStefano, AL, Psaty, BM, Dufouil, C, Catellier, DJ, Fazekas, F, Aspelund, T, Aulchenko, YS, Beiser, A, Rotter, JI, Tzourio, C, Shibata, DK, Tscherner, M, Harris, TB, Rivadeneira, F, Atwood, LD, Rice, K, Gottesman, RF, van Buchem, MA, Uitterlinden, A, Kelly-Hayes, M, Cushman, M, Zhu, YC, Boerwinkle, E, Gudnason, V, Hofman, B, Romero, JR, Lopez, O, Duijn, C, Au, R, Heckbert, SR, Wolf, PA, Mosley, TH, Seshadri, S, Breteler, M, Schmidt, R, Launer, LJ & Longstreth, WT 2010, 'Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium', Stroke, vol. 41, no. 2, pp. 210-217. https://doi.org/10.1161/STROKEAHA.109.569194

TY - JOUR

T1 - Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium

AU - Debette, S

AU - Bis, JC

AU - Fornage, M

AU - Schmidt, Heléna

AU - Ikram, Arfan

AU - Sigurdsson, S

AU - Heiss, G

AU - Struchalin, Maksim

AU - Smith, AV

AU - van der Lugt, Aad

AU - DeCarli, C

AU - Lumley, T

AU - Knopman, DS

AU - Enzinger, C

AU - Eiriksdottir, G

AU - Koudstaal, Peter

AU - DeStefano, AL

AU - Psaty, BM

AU - Dufouil, C

AU - Catellier, DJ

AU - Fazekas, F

AU - Aspelund, T

AU - Aulchenko, YS

AU - Beiser, A

AU - Rotter, JI

AU - Tzourio, C

AU - Shibata, DK

AU - Tscherner, M

AU - Harris, TB

AU - Rivadeneira, Fernando

AU - Atwood, LD

AU - Rice, K

AU - Gottesman, RF

AU - van Buchem, MA

AU - Uitterlinden, André

AU - Kelly-Hayes, M

AU - Cushman, M

AU - Zhu, YC

AU - Boerwinkle, E

AU - Gudnason, V

AU - Hofman, Bert

AU - Romero, JR

AU - Lopez, O

AU - Duijn, Cornelia

AU - Au, R (Rhoda)

AU - Heckbert, SR

AU - Wolf, PA

AU - Mosley, TH

AU - Seshadri, S

AU - Breteler, Monique

AU - Schmidt, R

AU - Launer, LJ (Lenore)

AU - Longstreth, WT

PY - 2010

Y1 - 2010

N2 - Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >= 1 MRI infarct). Results-The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P = 4.64 x 10(-7)). Highly suggestive associations (P < 1.0 x 10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2) > 0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions-This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed. (Stroke. 2010; 41: 210-217.)

AB - Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >= 1 MRI infarct). Results-The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P = 4.64 x 10(-7)). Highly suggestive associations (P < 1.0 x 10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2) > 0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions-This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed. (Stroke. 2010; 41: 210-217.)

U2 - 10.1161/STROKEAHA.109.569194

DO - 10.1161/STROKEAHA.109.569194

M3 - Article

C2 - 20044523

SN - 0039-2499

VL - 41

SP - 210

EP - 217

JO - Stroke

JF - Stroke

IS - 2

ER -