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

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. BrownBradford B. Worrall, Carl D. Langefeld, Daniel Woo, Jonathan Rosand

Neurology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2299-2301
Number of pages	3
Journal	Stroke; a journal of cerebral circulation
Volume	46
Issue number	8
DOIs	https://doi.org/10.1161/STROKEAHA.115.009838
State	Published - Aug 1 2015

Keywords

apolipoproteins E
cerebral hemorrhage
genome-wide association study

ASJC Scopus subject areas

Clinical Neurology
Cardiology and Cardiovascular Medicine
Advanced and Specialized Nursing

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10.1161/STROKEAHA.115.009838

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Radmanesh, F., Falcone, G. J., Anderson, C. D., McWilliams, D., Devan, W. J., Brown, W. M., Battey, T. W. K., Ayres, A. M., Raffeld, M. R., Schwab, K., Sun, G., Deka, R., Viswanathan, A., Goldstein, J. N., Greenberg, S. M., Tirschwell, D. L., Silliman, S. L., Selim, M., Meschia, J. F., ... Rosand, J. (2015). Rare Coding Variation and Risk of Intracerebral Hemorrhage. Stroke; a journal of cerebral circulation, 46(8), 2299-2301. https://doi.org/10.1161/STROKEAHA.115.009838

Radmanesh, F, Falcone, GJ, Anderson, CD, McWilliams, D, Devan, WJ, Brown, WM, Battey, TWK, Ayres, AM, Raffeld, MR, Schwab, K, Sun, G, Deka, R, Viswanathan, A, Goldstein, JN, Greenberg, SM, Tirschwell, DL, Silliman, SL, Selim, M, Meschia, JF, Brown, DL, Worrall, BB, Langefeld, CD, Woo, D & Rosand, J 2015, 'Rare Coding Variation and Risk of Intracerebral Hemorrhage', Stroke; a journal of cerebral circulation, vol. 46, no. 8, pp. 2299-2301. https://doi.org/10.1161/STROKEAHA.115.009838

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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",

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

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year = "2015",

month = aug,

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doi = "10.1161/STROKEAHA.115.009838",

language = "English (US)",

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T1 - Rare Coding Variation and Risk of Intracerebral Hemorrhage

AU - Radmanesh, Farid

AU - Falcone, Guido J.

AU - Anderson, Christopher D.

AU - McWilliams, David

AU - Devan, William J.

AU - Brown, W. Mark

AU - Battey, Thomas W.K.

AU - Ayres, Alison M.

AU - Raffeld, Miriam R.

AU - Schwab, Kristin

AU - Sun, Guangyun

AU - Deka, Ranjan

AU - Viswanathan, Anand

AU - Goldstein, Joshua N.

AU - Greenberg, Steven M.

AU - Tirschwell, David L.

AU - Silliman, Scott L.

AU - Selim, Magdy

AU - Meschia, James F.

AU - Brown, Devin L.

AU - Worrall, Bradford B.

AU - Langefeld, Carl D.

AU - Woo, Daniel

AU - Rosand, Jonathan

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

KW - apolipoproteins E

KW - cerebral hemorrhage

KW - genome-wide association study

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Rare Coding Variation and Risk of Intracerebral Hemorrhage

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