Rare Coding Variation and Risk of Intracerebral Hemorrhage

Farid Radmanesh; Guido J Falcone; Christopher D Anderson; David McWilliams; William J Devan; W Mark Brown; Thomas W K Battey; Alison M Ayres; Miriam R Raffeld; Kristin Schwab; Guangyun Sun; Ranjan Deka; Anand Viswanathan; Joshua N Goldstein; Steven M Greenberg; David L Tirschwell; Scott L Silliman; Magdy Selim; James F Meschia; Devin L Brown; Bradford B Worrall; Carl D Langefeld; Daniel Woo; Jonathan Rosand

doi:10.1161/STROKEAHA.115.009838

Rare Coding Variation and Risk of Intracerebral Hemorrhage

Stroke. 2015 Aug;46(8):2299-301. doi: 10.1161/STROKEAHA.115.009838. Epub 2015 Jun 25.

Authors

Farid Radmanesh¹, Guido J Falcone¹, Christopher D Anderson¹, David McWilliams¹, William J Devan¹, W Mark Brown¹, Thomas W K Battey¹, Alison M Ayres¹, Miriam R Raffeld¹, Kristin Schwab¹, Guangyun Sun¹, Ranjan Deka¹, Anand Viswanathan¹, Joshua N Goldstein¹, Steven M Greenberg¹, David L Tirschwell¹, Scott L Silliman¹, Magdy Selim¹, James F Meschia¹, Devin L Brown¹, Bradford B Worrall¹, Carl D Langefeld¹, Daniel Woo¹, Jonathan Rosand²

Affiliations

¹ From the Center for Human Genetic Research (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.), J. Philip Kistler Stroke Research Center (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., A.M.A., M.R.R., K.S., A.V., S.M.G., J.R.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.); Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC (D.M., W.M.B., C.D.L.); Quinnipiac University, Frank H. Netter MD School of Medicine, Hamden, CT (W.J.D.); Department of Environmental Health (G.S., R.D.) and Department of Neurology and Rehabilitation (D.W.), University of Cincinnati College of Medicine, OH; Department of Neurology, Harborview Medical Center, University of Washington, Seattle (D.L.T.); Department of Neurology, University of Florida College of Medicine, Jacksonville (S.L.S.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.S.); Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Department of Neurology, University of Michigan Health System, Ann Arbor (D.L.B.); and Departments of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville (B.B.W.).
² From the Center for Human Genetic Research (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.), Division of Neurocritical Care and Emergency Neurology, Department of Neurology (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.), J. Philip Kistler Stroke Research Center (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., A.M.A., M.R.R., K.S., A.V., S.M.G., J.R.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (F.R., G.J.F., C.D.A., W.J.D., T.W.K.B., M.R.R., J.R.); Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC (D.M., W.M.B., C.D.L.); Quinnipiac University, Frank H. Netter MD School of Medicine, Hamden, CT (W.J.D.); Department of Environmental Health (G.S., R.D.) and Department of Neurology and Rehabilitation (D.W.), University of Cincinnati College of Medicine, OH; Department of Neurology, Harborview Medical Center, University of Washington, Seattle (D.L.T.); Department of Neurology, University of Florida College of Medicine, Jacksonville (S.L.S.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.S.); Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Department of Neurology, University of Michigan Health System, Ann Arbor (D.L.B.); and Departments of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville (B.B.W.). jrosand@partners.org.

Abstract

Background and purpose: Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage.

Methods: A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed.

Results: No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing.

Conclusions: Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for sufficient power except for loci with large effects.

Keywords: apolipoproteins E; cerebral hemorrhage; genome-wide association study.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Cerebral Hemorrhage / diagnosis
Cerebral Hemorrhage / epidemiology
Cerebral Hemorrhage / genetics*
Female
Genetic Predisposition to Disease / epidemiology
Genetic Predisposition to Disease / genetics*
Genetic Variation / genetics*
Genome-Wide Association Study / methods*
Humans
Male
Middle Aged
Risk Factors

Abstract

Publication types

MeSH terms

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