Variants at APOE influence risk of deep and lobar intracerebral hemorrhage

Alessandro Biffi, Akshata Sonni, Christopher D. Anderson, Brett Kissela, Jeremiasz M. Jagiella, Helena Schmidt, Jordi Jimenez-Conde, Björn M. Hansen, Israel Fernandez-Cadenas, Lynelle Cortellini, Alison Ayres, Kristin Schwab, Karol Juchniewicz, Andrzej Urbanik, Natalia S. Rost, Anand Viswanathan, Thomas Seifert-Held, Eva Maria Stoegerer, Marta Tomás, Raquel Rabionet & 15 others Xavier P. Estivill, Devin L. Brown, Scott L. Silliman, Magdy Selim, Bradford B. Worrall, James F. Meschia, Joan Montaner, Arne Lindgren, Jaume Roquer, Reinhold Schmidt, Steven M. Greenberg, Agnieszka Slowik, Joseph P. Broderick, Daniel Woo, Jonathan Rosand

Research output: Contribution to journalArticle

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Abstract

Objective: Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 × 10-10; and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 × 10-11, respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 × 10-4). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.

Original languageEnglish
Pages (from-to)934-943
Number of pages10
JournalAnnals of Neurology
Volume68
Issue number6
DOIs
Publication statusPublished - Dec 2010
Externally publishedYes

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Cerebral Hemorrhage
Alleles
Odds Ratio
Confidence Intervals
Genome
Cerebral Amyloid Angiopathy
Genetic Models
Genetic Association Studies
Amyloid
Sample Size
Population
Genotype

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Biffi, A., Sonni, A., Anderson, C. D., Kissela, B., Jagiella, J. M., Schmidt, H., ... Rosand, J. (2010). Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Annals of Neurology, 68(6), 934-943. https://doi.org/10.1002/ana.22134

Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. / Biffi, Alessandro; Sonni, Akshata; Anderson, Christopher D.; Kissela, Brett; Jagiella, Jeremiasz M.; Schmidt, Helena; Jimenez-Conde, Jordi; Hansen, Björn M.; Fernandez-Cadenas, Israel; Cortellini, Lynelle; Ayres, Alison; Schwab, Kristin; Juchniewicz, Karol; Urbanik, Andrzej; Rost, Natalia S.; Viswanathan, Anand; Seifert-Held, Thomas; Stoegerer, Eva Maria; Tomás, Marta; Rabionet, Raquel; Estivill, Xavier P.; Brown, Devin L.; Silliman, Scott L.; Selim, Magdy; Worrall, Bradford B.; Meschia, James F.; Montaner, Joan; Lindgren, Arne; Roquer, Jaume; Schmidt, Reinhold; Greenberg, Steven M.; Slowik, Agnieszka; Broderick, Joseph P.; Woo, Daniel; Rosand, Jonathan.

In: Annals of Neurology, Vol. 68, No. 6, 12.2010, p. 934-943.

Research output: Contribution to journalArticle

Biffi, A, Sonni, A, Anderson, CD, Kissela, B, Jagiella, JM, Schmidt, H, Jimenez-Conde, J, Hansen, BM, Fernandez-Cadenas, I, Cortellini, L, Ayres, A, Schwab, K, Juchniewicz, K, Urbanik, A, Rost, NS, Viswanathan, A, Seifert-Held, T, Stoegerer, EM, Tomás, M, Rabionet, R, Estivill, XP, Brown, DL, Silliman, SL, Selim, M, Worrall, BB, Meschia, JF, Montaner, J, Lindgren, A, Roquer, J, Schmidt, R, Greenberg, SM, Slowik, A, Broderick, JP, Woo, D & Rosand, J 2010, 'Variants at APOE influence risk of deep and lobar intracerebral hemorrhage', Annals of Neurology, vol. 68, no. 6, pp. 934-943. https://doi.org/10.1002/ana.22134
Biffi A, Sonni A, Anderson CD, Kissela B, Jagiella JM, Schmidt H et al. Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Annals of Neurology. 2010 Dec;68(6):934-943. https://doi.org/10.1002/ana.22134
Biffi, Alessandro ; Sonni, Akshata ; Anderson, Christopher D. ; Kissela, Brett ; Jagiella, Jeremiasz M. ; Schmidt, Helena ; Jimenez-Conde, Jordi ; Hansen, Björn M. ; Fernandez-Cadenas, Israel ; Cortellini, Lynelle ; Ayres, Alison ; Schwab, Kristin ; Juchniewicz, Karol ; Urbanik, Andrzej ; Rost, Natalia S. ; Viswanathan, Anand ; Seifert-Held, Thomas ; Stoegerer, Eva Maria ; Tomás, Marta ; Rabionet, Raquel ; Estivill, Xavier P. ; Brown, Devin L. ; Silliman, Scott L. ; Selim, Magdy ; Worrall, Bradford B. ; Meschia, James F. ; Montaner, Joan ; Lindgren, Arne ; Roquer, Jaume ; Schmidt, Reinhold ; Greenberg, Steven M. ; Slowik, Agnieszka ; Broderick, Joseph P. ; Woo, Daniel ; Rosand, Jonathan. / Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. In: Annals of Neurology. 2010 ; Vol. 68, No. 6. pp. 934-943.
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abstract = "Objective: Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95{\%} confidence interval [CI] = 1.50-2.23, p = 6.6 × 10-10; and OR = 2.20, 95{\%}CI = 1.85-2.63, p = 2.4 × 10-11, respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95{\%} CI = 1.08-1.36, p = 2.6 × 10-4). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.",
author = "Alessandro Biffi and Akshata Sonni and Anderson, {Christopher D.} and Brett Kissela and Jagiella, {Jeremiasz M.} and Helena Schmidt and Jordi Jimenez-Conde and Hansen, {Bj{\"o}rn M.} and Israel Fernandez-Cadenas and Lynelle Cortellini and Alison Ayres and Kristin Schwab and Karol Juchniewicz and Andrzej Urbanik and Rost, {Natalia S.} and Anand Viswanathan and Thomas Seifert-Held and Stoegerer, {Eva Maria} and Marta Tom{\'a}s and Raquel Rabionet and Estivill, {Xavier P.} and Brown, {Devin L.} and Silliman, {Scott L.} and Magdy Selim and Worrall, {Bradford B.} and Meschia, {James F.} and Joan Montaner and Arne Lindgren and Jaume Roquer and Reinhold Schmidt and Greenberg, {Steven M.} and Agnieszka Slowik and Broderick, {Joseph P.} and Daniel Woo and Jonathan Rosand",
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T1 - Variants at APOE influence risk of deep and lobar intracerebral hemorrhage

AU - Biffi, Alessandro

AU - Sonni, Akshata

AU - Anderson, Christopher D.

AU - Kissela, Brett

AU - Jagiella, Jeremiasz M.

AU - Schmidt, Helena

AU - Jimenez-Conde, Jordi

AU - Hansen, Björn M.

AU - Fernandez-Cadenas, Israel

AU - Cortellini, Lynelle

AU - Ayres, Alison

AU - Schwab, Kristin

AU - Juchniewicz, Karol

AU - Urbanik, Andrzej

AU - Rost, Natalia S.

AU - Viswanathan, Anand

AU - Seifert-Held, Thomas

AU - Stoegerer, Eva Maria

AU - Tomás, Marta

AU - Rabionet, Raquel

AU - Estivill, Xavier P.

AU - Brown, Devin L.

AU - Silliman, Scott L.

AU - Selim, Magdy

AU - Worrall, Bradford B.

AU - Meschia, James F.

AU - Montaner, Joan

AU - Lindgren, Arne

AU - Roquer, Jaume

AU - Schmidt, Reinhold

AU - Greenberg, Steven M.

AU - Slowik, Agnieszka

AU - Broderick, Joseph P.

AU - Woo, Daniel

AU - Rosand, Jonathan

PY - 2010/12

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N2 - Objective: Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 × 10-10; and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 × 10-11, respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 × 10-4). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.

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