Objective Prior studies investigating the association between APOE alleles ε2 / ε4 and risk of Intracerebral Hemorrhage (ICH) have been inconsistent, 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 2,189 ICH cases and 4,041 controls from seven 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 and 357 controls) had available genome-wide data to adjust for population stratification. Results 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 CAA ICH uncovered a stronger effect. 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.

Background-Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. Methods and Results-Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, Pϭ1.2ϫ10 Ϫ20) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. Conclusions-We Clinical Perspective on p 984We recently participated in a genome-wide association study that identified a disease-susceptibility locus for AF on chromosome 4q25 in individuals of European and Asian descent. 5 We replicated the association between the most significantly associated single-nucleotide polymorphism (SNP), rs2200733, and AF in a subsequent study of 3508 subjects with AF and 12 173 control subjects from 4 additional cohorts of European ancestry. 6 A meta-analysis of the results from both studies revealed an odds ratio (OR) of 1.9 for the rs2200733 risk allele (95% confidence interval [CI] 1.60 to 2.26, Pϭ3.3ϫ10 Ϫ13 ). 6 We and others have again replicated the chromosome 4q25 AF susceptibility locus in subsequent genome-wide association studies for AF. [7][8][9] In the present study, we sought to identify whether there are multiple AF susceptibility signals at the 4q25 locus in individuals of European ancestry by performing fine mapping of common SNPs in the region and replicating associations in independent study samples. We further sought to determine whether the consideration of multiple markers associated with AF at this locus could further refine the association signal. Methods Study SamplesDetailed descriptions of the study cohorts are provided in the online-only Data Supplement. Individuals in the discovery stage of the analysis were drawn from 2 different samples at the Massachusetts General Hospital (MGH) and pooled for analysis. These samples included patients with lone AF referred to the Cardiac Arrhythmia Service starting in June 2001 in whom AF was documented by ECG before 66 years of age and...