Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage

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• 作者：Daniel Woo¹ ; ³⁴ ; ^{daniel.woo@uc.edu" class="auth_mail} ; Guido J. Falcone² ; ³ ; ⁴ ; ⁵ ; ⁶ ; ³⁴ ; William J. Devan² ; ³ ; ⁴ ; ⁵ ; W. Mark Brown⁷ ; Alessandro Biffi² ; ³ ; ⁴ ; ⁵ ; Timothy D. Howard⁷ ; Christopher D. Anderson² ; ³ ; ⁴ ; ⁵ ; H. Bart Brouwers² ; ³ ; ⁴ ; ⁵ ; Valerie Valant² ; ³ ; ⁴ ; ⁵ ; Thomas W.K. Battey² ; ³ ; ⁴ ; ⁵ ; Farid Radmanesh² ; ³ ; ⁴ ; ⁵ ; Miriam R. Raffeld² ; ³ ; ⁴ ; ⁵ ; Sylvia Baedorf-Kassis² ; ³ ; ⁴ ; ⁵ ; Ranjan Deka⁸ ; Jessica G. Woo⁹ ; Lisa J. Martin¹⁰ ; Mary Haverbusch¹ ; Charles J. Moomaw¹ ; Guangyun Sun⁸ ; Joseph P. Broderick¹ ; Matthew L. Flaherty¹ ; Sharyl R. Martini¹ ; Dawn O. Kleindorfer¹ ; Brett Kissela¹ ; Mary E. Comeau⁷ ; Jeremiasz M. Jagiella¹¹ ; Helena Schmidt¹² ; Paul Freudenberger¹² ; Alexander Pichler¹³ ; Christian Enzinger¹³ ; ¹⁴ ; Bjö ; rn M. Hansen¹⁵ ; ¹⁶ ; Bo Norrving¹⁵ ; ¹⁶ ; Jordi Jimenez-Conde¹⁷ ; ¹⁸ ; Eva Giralt-Steinhauer¹⁷ ; ¹⁸ ; Roberto Elosua¹⁷ ; ¹⁸ ; Elisa Cuadrado-Godia¹⁷ ; ¹⁸ ; Carolina Soriano¹⁷ ; ¹⁸ ; Jaume Roquer¹⁷ ; ¹⁸ ; Peter Kraft⁶ ; Alison M. Ayres⁴ ; Kristin Schwab⁴ ; Jacob L. McCauley¹⁹ ; Joanna Pera¹¹ ; Andrzej Urbanik²⁰ ; Natalia S. Rost² ; ³ ; ⁴ ; ⁵ ; Joshua N. Goldstein²¹ ; Anand Viswanathan⁴ ; Eva-Maria Stö ; gerer¹³ ; David L. Tirschwell²² ; Magdy Selim²³ ; Devin L. Brown²⁴ ; Scott L. Silliman²⁵ ; Bradford B. Worrall²⁶ ; James F. Meschia²⁷ ; Chelsea S. Kidwell²⁸ ; Joan Montaner²⁹ ; Israel Fernandez-Cadenas²⁹ ; ³⁰ ; Pilar Delgado²⁹ ; Rainer Malik³¹ ; ³² ; Martin Dichgans³¹ ; ³² ; Steven M. Greenberg⁴ ; Peter M. Rothwell³³ ; Arne Lindgren¹⁵ ; ¹⁶ ; Agnieszka Slowik¹¹ ; Reinhold Schmidt¹³ ; Carl D. Langefeld⁷ ; ³⁵ ; Jonathan Rosand² ; ³ ; ⁴ ; ⁵ ; ³⁵ ; ^{jrosand@partners.org" class="auth_mail} ; the International Stroke Genetics Consortium
• 刊名：The American Journal of Human Genetics
• 出版年：3 April, 2014
• 年：2014
• 卷：94
• 期：4
• 页码：511-521
• 全文大小：1391 K

文摘

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聽脳 10^鈭? 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聽脳 10^鈭?); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6聽脳 10^鈭?). 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聽脳 10^鈭?; meta-analysis p = 2.2聽脳 10^鈭?0) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6聽脳 10^鈭?). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.