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Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage
Open accessAbstract
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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Metadata
- Authors
- 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., Broderick, J. P., Flaherty, M. L., Martini, S. R., Kleindorfer, D. O., Kissela, B., Comeau, M. E., Jagiella, J. M., Schmidt, H., Freudenberger, P., Pichler, A., Enzinger, C., Hansen, B. M., Norrving, B., Jimenez-Conde, J., Giralt-Steinhauer, E., Elosua, R., Cuadrado-Godia, E., Soriano, C., Roquer, J., Kraft, P., Ayres, A. M., Schwab, K., McCauley, J. L., Pera, J., Urbanik, A., Rost, N. S., Goldstein, J. N., Viswanathan, A., Stögerer, E.-M., Tirschwell, D. L., Selim, M., Brown, D. L., Silliman, S. L., Worrall, B. B., Meschia, J. F., Kidwell, C. S., Montaner, J., Fernandez-Cadenas, I., Delgado, P., Malik, R., Dichgans, M., Greenberg, S. M., Rothwell, P. M., Lindgren, A., Slowik, A., Schmidt, R., Langefeld, C. D., & Rosand, J.
- Affiliations
- University of Cincinnati (US)
- Broad Institute (US)
- Wake Forest University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Jagiellonian University (PL)
- Medical University of Graz (AT)
- Lund University (SE)
- Universitat Autònoma de Barcelona (ES)
- Harvard University (US)
- Massachusetts General Hospital (US)
- University of Miami (US)
- University of Washington (US)
- Beth Israel Deaconess Medical Center (US)
- Michigan Medicine (US)
- University of Florida (US)
- University of Virginia Health System (US)
- Mayo Clinic (US)
- University of Arizona (US)
- LMU Klinikum (DE)
- University of Oxford (GB)
- Corresponding author
- Woo, Daniel
- Rosand, Jonathan
- ORCID
- Woo, Daniel
- Falcone, Guido J.
- Biffi, Alessandro
- Howard, Timothy D.
- Anderson, Christopher D.
- Brouwers, H. Bart
- Radmanesh, Farid
- Raffeld, Miriam R.
- Deka, Ranjan
- Woo, Jessica G.
- Martin, Lisa J.
- Haverbusch, Mary
- Moomaw, Charles J.
- Broderick, Joseph P.
- Flaherty, Matthew L.
- Martini, Sharyl R.
- Kleindorfer, Dawn O.
- Comeau, Mary E.
- Jagiella, Jeremiasz M.
- Schmidt, Helena
- Pichler, Alexander
- Enzinger, Christian
- Hansen, Björn M.
- Norrving, Bo
- Roquer, Jaume
- Kraft, Peter
- Ayres, Alison M.
- Schwab, Kristin
- McCauley, Jacob L.
- Pera, Joanna
- Rost, Natalia S.
- Goldstein, Joshua N.
- Viswanathan, Anand
- Tirschwell, David L.
- Selim, Magdy
- Brown, Devin L.
- Worrall, Bradford B.
- Meschia, James F.
- Montaner, Joan
- Delgado, Pilar
- Malik, Rainer
- Dichgans, Martin
- Greenberg, Steven M.
- Rothwell, Peter M.
- Lindgren, Arne
- Schmidt, Reinhold
- Langefeld, Carl D.
- Rosand, Jonathan
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 94
- Issue
- 4
- Pages
- 511-521
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3980413
- OpenAlex
- W2131293296
- Cited by
- 290
- References
- 55
- Citations by year
- 2026: 8 · 2025: 23 · 2024: 35 · 2023: 36 · 2022: 29 · 2021: 34 · 2020: 24 · 2019: 27 · 2018: 26 · 2017: 15 · 2016: 11 · 2015: 14 · 2014: 6
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, other-oa)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by-nc-nd)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institutes of Health (NS30678, NS36695)
- Region Skåne
- Blue Cross Blue Shield of Michigan Foundation
- Michigan Department of Community Health
- Vetenskapsrådet (K2010-61X-20378-04-3)
- Instituto de Salud Carlos III (PI051737)
- STROKE-Riksförbundet
- National Institute for Health and Care Research
- Lunds Universitet
- American Brain Foundation (5K23NS059774)
- University of Michigan
- Wellcome Trust (R01 HL098065, R01 NS062675, R01 NS070941, R18 HS017690, U01 NS074425)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Clinical Neurology › Cerebrovascular and genetic disorders
- Keywords
- intracerebral hemorrhage, genetic susceptibility, 1q22, lobar hemorrhage, stroke subtypes, case ascertainment, European ancestry
- MeSH terms
- Cerebral Hemorrhage, Chromosomes, Human, Pair 1, Humans, Case-Control Studies, Genetic Predisposition to Disease, Quantitative Trait Loci, Genome-Wide Association Study
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