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, Stella 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)511-521
Number of pages11
JournalAmerican Journal of Human Genetics
Volume94
Issue number4
DOIs
StatePublished - Apr 3 2014

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Genome-Wide Association Study
Cerebral Hemorrhage
Meta-Analysis
Blood Vessels
Odds Ratio
Brain
Stroke
Genotype
Tomography
Genome
Pathology

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. / Woo, Daniel; Falcone, Guido J.; Devan, William J.; Brown, W. Mark; Biffi, Alessandro; Howard, Timothy D.; Anderson, Christopher D.; Brouwers, H. Bart; Valant, Valerie; Battey, Thomas W K; Radmanesh, Farid; Raffeld, Miriam R.; Baedorf-Kassis, Sylvia; Deka, Ranjan; Woo, Jessica G.; Martin, Lisa J.; Haverbusch, Mary; Moomaw, Charles J.; Sun, Guangyun; Broderick, Joseph P.; Flaherty, Matthew L.; Martini, Sharyl R.; Kleindorfer, Dawn O.; Kissela, Brett; Comeau, Mary E.; Jagiella, Jeremiasz M.; Schmidt, Helena; Freudenberger, Paul; Pichler, Alexander; Enzinger, Christian; Hansen, Björn M.; Norrving, Bo; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Elosua, Roberto; Cuadrado-Godia, Elisa; Soriano, Carolina; Roquer, Jaume; Kraft, Peter; Ayres, Alison M.; Schwab, Kristin; McCauley, Jacob L.; Pera, Joanna; Urbanik, Andrzej; Rost, Natalia S.; Goldstein, Joshua N.; Viswanathan, Anand; Stögerer, Eva Maria; Tirschwell, David L.; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Worrall, Bradford B.; Meschia, James F.; Kidwell, Stella; Montaner, Joan; Fernandez-Cadenas, Israel; Delgado, Pilar; Malik, Rainer; Dichgans, Martin; Greenberg, Steven M.; Rothwell, Peter M.; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Langefeld, Carl D.; Rosand, Jonathan.

In: American Journal of Human Genetics, Vol. 94, No. 4, 03.04.2014, p. 511-521.

Research output: Contribution to journalArticle

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, S, 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
Woo, Daniel ; Falcone, Guido J. ; Devan, William J. ; Brown, W. Mark ; Biffi, Alessandro ; Howard, Timothy D. ; Anderson, Christopher D. ; Brouwers, H. Bart ; Valant, Valerie ; Battey, Thomas W K ; Radmanesh, Farid ; Raffeld, Miriam R. ; Baedorf-Kassis, Sylvia ; Deka, Ranjan ; Woo, Jessica G. ; Martin, Lisa J. ; Haverbusch, Mary ; Moomaw, Charles J. ; Sun, Guangyun ; Broderick, Joseph P. ; Flaherty, Matthew L. ; Martini, Sharyl R. ; Kleindorfer, Dawn O. ; Kissela, Brett ; Comeau, Mary E. ; Jagiella, Jeremiasz M. ; Schmidt, Helena ; Freudenberger, Paul ; Pichler, Alexander ; Enzinger, Christian ; Hansen, Björn M. ; Norrving, Bo ; Jimenez-Conde, Jordi ; Giralt-Steinhauer, Eva ; Elosua, Roberto ; Cuadrado-Godia, Elisa ; Soriano, Carolina ; Roquer, Jaume ; Kraft, Peter ; Ayres, Alison M. ; Schwab, Kristin ; McCauley, Jacob L. ; Pera, Joanna ; Urbanik, Andrzej ; Rost, Natalia S. ; Goldstein, Joshua N. ; Viswanathan, Anand ; Stögerer, Eva Maria ; Tirschwell, David L. ; Selim, Magdy ; Brown, Devin L. ; Silliman, Scott L. ; Worrall, Bradford B. ; Meschia, James F. ; Kidwell, Stella ; Montaner, Joan ; Fernandez-Cadenas, Israel ; Delgado, Pilar ; Malik, Rainer ; Dichgans, Martin ; Greenberg, Steven M. ; Rothwell, Peter M. ; Lindgren, Arne ; Slowik, Agnieszka ; Schmidt, Reinhold ; Langefeld, Carl D. ; Rosand, Jonathan. / Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 4. pp. 511-521.
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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.",
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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, Stella

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.

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.

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