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 RabionetXavier 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 journalArticlepeer-review

175 Scopus citations


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 (US)
Pages (from-to)934-943
Number of pages10
JournalAnnals of neurology
Issue number6
StatePublished - Dec 2010

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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