Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage

Daniel Woo; Guido J. Falcone; William J. Devan; W. Mark Brown; Alessandro Biffi; Timothy D. Howard; Christopher D. Anderson; H. Bart Brouwers; Valerie Valant; Thomas W.K. Battey; Farid Radmanesh; Miriam R. Raffeld; Sylvia Baedorf-Kassis; Ranjan Deka; Jessica G. Woo; Lisa J. Martin; Mary Haverbusch; Charles J. Moomaw; Guangyun Sun; Joseph P. Broderick; Matthew L. Flaherty; Sharyl R. Martini; Dawn O. Kleindorfer; Brett Kissela; Mary E. Comeau; Jeremiasz M. Jagiella; Helena Schmidt; Paul Freudenberger; Alexander Pichler; Christian Enzinger; Björn M. Hansen; Bo Norrving; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano; Jaume Roquer; Peter Kraft; Alison M. Ayres; Kristin Schwab; Jacob L. McCauley; Joanna Pera; Andrzej Urbanik; Natalia S. Rost; Joshua N. Goldstein; Anand Viswanathan; Eva Maria Stögerer; David L. Tirschwell; Magdy Selim; Devin L. Brown; Scott L. Silliman; Bradford B. Worrall; James F. Meschia; Chelsea S. Kidwell; Joan Montaner; Israel Fernandez-Cadenas; Pilar Delgado; Rainer Malik; Martin Dichgans; Steven M. Greenberg; Peter M. Rothwell; Arne Lindgren; Agnieszka Slowik; Reinhold Schmidt; Carl D. Langefeld; Jonathan Rosand

doi:10.1016/j.ajhg.2014.02.012

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage

Daniel Woo, Guido J. Falcone, William J. Devan, W. Mark Brown, Alessandro Biffi, Timothy D. Howard, Christopher D. Anderson, H. Bart Brouwers, Valerie Valant, Thomas W.K. Battey, Farid Radmanesh, Miriam R. Raffeld, Sylvia Baedorf-Kassis, Ranjan Deka, Jessica G. Woo, Lisa J. Martin, Mary Haverbusch, Charles J. Moomaw, Guangyun Sun, Joseph P. BroderickMatthew L. Flaherty, Sharyl R. Martini, Dawn O. Kleindorfer, Brett Kissela, Mary E. Comeau, Jeremiasz M. Jagiella, Helena Schmidt, Paul Freudenberger, Alexander Pichler, Christian Enzinger, Björn M. Hansen, Bo Norrving, Jordi Jimenez-Conde, Eva Giralt-Steinhauer, Roberto Elosua, Elisa Cuadrado-Godia, Carolina Soriano, Jaume Roquer, Peter Kraft, Alison M. Ayres, Kristin Schwab, Jacob L. McCauley, Joanna Pera, Andrzej Urbanik, Natalia S. Rost, Joshua N. Goldstein, Anand Viswanathan, Eva Maria Stögerer, David L. Tirschwell, Magdy Selim, Devin L. Brown, Scott L. Silliman, Bradford B. Worrall, James F. Meschia, Chelsea S. Kidwell, Joan Montaner, Israel Fernandez-Cadenas, Pilar Delgado, Rainer Malik, Martin Dichgans, Steven M. Greenberg, Peter M. Rothwell, Arne Lindgren, Agnieszka Slowik, Reinhold Schmidt, Carl D. Langefeld, Jonathan Rosand

Department of Medicine

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193 Citations (Scopus)

Abstract

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10-6 was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10-8); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10-8). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10-4; meta-analysis p = 2.2 × 10 -10) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10-5). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. © 2014 The American Society of Human Genetics.

Original language	English
Pages (from-to)	511-521
Journal	American Journal of Human Genetics
Volume	94
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2014.02.012
Publication status	Published - 3 Apr 2014

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Woo, D., Falcone, G. J., Devan, W. J., Brown, W. M., Biffi, A., Howard, T. D., Anderson, C. D., Brouwers, H. B., Valant, V., Battey, T. W. K., Radmanesh, F., Raffeld, M. R., Baedorf-Kassis, S., Deka, R., Woo, J. G., Martin, L. J., Haverbusch, M., Moomaw, C. J., Sun, G., ... Rosand, J. (2014). Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. American Journal of Human Genetics, 94(4), 511-521. https://doi.org/10.1016/j.ajhg.2014.02.012

@article{cce91a16da534ad0a14a26c0f6ee55d5,

title = "Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage",

abstract = "Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10-6 was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10-8); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10-8). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10-4; meta-analysis p = 2.2 × 10 -10) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10-5). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. {\textcopyright} 2014 The American Society of Human Genetics.",

author = "Daniel Woo and Falcone, {Guido J.} and Devan, {William J.} and Brown, {W. Mark} and Alessandro Biffi and Howard, {Timothy D.} and Anderson, {Christopher D.} and Brouwers, {H. Bart} and Valerie Valant and Battey, {Thomas W.K.} and Farid Radmanesh and Raffeld, {Miriam R.} and Sylvia Baedorf-Kassis and Ranjan Deka and Woo, {Jessica G.} and Martin, {Lisa J.} and Mary Haverbusch and Moomaw, {Charles J.} and Guangyun Sun and Broderick, {Joseph P.} and Flaherty, {Matthew L.} and Martini, {Sharyl R.} and Kleindorfer, {Dawn O.} and Brett Kissela and Comeau, {Mary E.} and Jagiella, {Jeremiasz M.} and Helena Schmidt and Paul Freudenberger and Alexander Pichler and Christian Enzinger and Hansen, {Bj{\"o}rn M.} and Bo Norrving and Jordi Jimenez-Conde and Eva Giralt-Steinhauer and Roberto Elosua and Elisa Cuadrado-Godia and Carolina Soriano and Jaume Roquer and Peter Kraft and Ayres, {Alison M.} and Kristin Schwab and McCauley, {Jacob L.} and Joanna Pera and Andrzej Urbanik and Rost, {Natalia S.} and Goldstein, {Joshua N.} and Anand Viswanathan and St{\"o}gerer, {Eva Maria} and Tirschwell, {David L.} and Magdy Selim and Brown, {Devin L.} and Silliman, {Scott L.} and Worrall, {Bradford B.} and Meschia, {James F.} and Kidwell, {Chelsea S.} and Joan Montaner and Israel Fernandez-Cadenas and Pilar Delgado and Rainer Malik and Martin Dichgans and Greenberg, {Steven M.} and Rothwell, {Peter M.} and Arne Lindgren and Agnieszka Slowik and Reinhold Schmidt and Langefeld, {Carl D.} and Jonathan Rosand",

year = "2014",

month = apr,

day = "3",

doi = "10.1016/j.ajhg.2014.02.012",

language = "English",

volume = "94",

pages = "511--521",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

Woo, D, Falcone, GJ, Devan, WJ, Brown, WM, Biffi, A, Howard, TD, Anderson, CD, Brouwers, HB, Valant, V, Battey, TWK, Radmanesh, F, Raffeld, MR, Baedorf-Kassis, S, Deka, R, Woo, JG, Martin, LJ, Haverbusch, M, Moomaw, CJ, Sun, G, Broderick, JP, Flaherty, ML, Martini, SR, Kleindorfer, DO, Kissela, B, Comeau, ME, Jagiella, JM, Schmidt, H, Freudenberger, P, Pichler, A, Enzinger, C, Hansen, BM, Norrving, B, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano, C, Roquer, J, Kraft, P, Ayres, AM, Schwab, K, McCauley, JL, Pera, J, Urbanik, A, Rost, NS, Goldstein, JN, Viswanathan, A, Stögerer, EM, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Montaner, J, Fernandez-Cadenas, I, Delgado, P, Malik, R, Dichgans, M, Greenberg, SM, Rothwell, PM, Lindgren, A, Slowik, A, Schmidt, R, Langefeld, CD & Rosand, J 2014, 'Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage', American Journal of Human Genetics, vol. 94, no. 4, pp. 511-521. https://doi.org/10.1016/j.ajhg.2014.02.012

TY - JOUR

T1 - Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage

AU - Woo, Daniel

AU - Falcone, Guido J.

AU - Devan, William J.

AU - Brown, W. Mark

AU - Biffi, Alessandro

AU - Howard, Timothy D.

AU - Anderson, Christopher D.

AU - Brouwers, H. Bart

AU - Valant, Valerie

AU - Battey, Thomas W.K.

AU - Radmanesh, Farid

AU - Raffeld, Miriam R.

AU - Baedorf-Kassis, Sylvia

AU - Deka, Ranjan

AU - Woo, Jessica G.

AU - Martin, Lisa J.

AU - Haverbusch, Mary

AU - Moomaw, Charles J.

AU - Sun, Guangyun

AU - Broderick, Joseph P.

AU - Flaherty, Matthew L.

AU - Martini, Sharyl R.

AU - Kleindorfer, Dawn O.

AU - Kissela, Brett

AU - Comeau, Mary E.

AU - Jagiella, Jeremiasz M.

AU - Schmidt, Helena

AU - Freudenberger, Paul

AU - Pichler, Alexander

AU - Enzinger, Christian

AU - Hansen, Björn M.

AU - Norrving, Bo

AU - Jimenez-Conde, Jordi

AU - Giralt-Steinhauer, Eva

AU - Elosua, Roberto

AU - Cuadrado-Godia, Elisa

AU - Soriano, Carolina

AU - Roquer, Jaume

AU - Kraft, Peter

AU - Ayres, Alison M.

AU - Schwab, Kristin

AU - McCauley, Jacob L.

AU - Pera, Joanna

AU - Urbanik, Andrzej

AU - Rost, Natalia S.

AU - Goldstein, Joshua N.

AU - Viswanathan, Anand

AU - Stögerer, Eva Maria

AU - Tirschwell, David L.

AU - Selim, Magdy

AU - Brown, Devin L.

AU - Silliman, Scott L.

AU - Worrall, Bradford B.

AU - Meschia, James F.

AU - Kidwell, Chelsea S.

AU - Montaner, Joan

AU - Fernandez-Cadenas, Israel

AU - Delgado, Pilar

AU - Malik, Rainer

AU - Dichgans, Martin

AU - Greenberg, Steven M.

AU - Rothwell, Peter M.

AU - Lindgren, Arne

AU - Slowik, Agnieszka

AU - Schmidt, Reinhold

AU - Langefeld, Carl D.

AU - Rosand, Jonathan

PY - 2014/4/3

Y1 - 2014/4/3

N2 - Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10-6 was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10-8); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10-8). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10-4; meta-analysis p = 2.2 × 10 -10) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10-5). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. © 2014 The American Society of Human Genetics.

AB - Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10-6 was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10-8); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10-8). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10-4; meta-analysis p = 2.2 × 10 -10) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10-5). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. © 2014 The American Society of Human Genetics.

U2 - 10.1016/j.ajhg.2014.02.012

DO - 10.1016/j.ajhg.2014.02.012

M3 - Article

SN - 0002-9297

VL - 94

SP - 511

EP - 521

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage

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