Response: CALHM1 Association with Alzheimer's Disease Risk

ranging from 0.15 to 0.84). Stratification by age of AD onset (using 65 years as cutoff) or APOE ε4-genotype did not appreciably change these results (data not shown; stratified analyses were not possible in the GWAS samples as no onset age or APOE ε4 data were supplied). Effect size estimates indicated insignificant ORs that were opposite in direction to those reported by Dreses-Werringloer et al. (2008) in six of the eight samples (see Figure S1). Accordingly, summary ORs calculated across the newly genotyped samples in our study (labeled “This study” in Figure S1) were insignificant (OR = 0.94 [95% CI: 0.83–1.07], p = 0.4) and tended toward null when combined with the published GWAS genotype data (“All follow-up”; OR = 0.99 [95% CI: 0.91–1.09], p = 0.9). Upon combining these data with the results of the original study (“All studies”), that is, generating a meta-analysis on all ~11,700 currently available subjects, the overall summary OR became insignificant as well (OR = 1.13 [95% CI: 0.99–1.27], p = 0.06). Using rs1555823 (instead of rs2986030) as proxy for the rs2986017 (Pro86Leu) variant in the GWAS samples revealed even less pronounced and less significant overall effects (data not shown). Thus, we have independently assessed the potential association between AD risk and the rs2986017 (Pro86Leu) variant in the CALHM1 gene in a large number of independent datasets, including AD families in which the original chromosome 10q24 linkage signal was identified (Bertram et al., 2000). Despite good to excellent power to detect genetic effect sizes on the order described by Dreses-Werringloer et al. (2008), no association between CALHM1 and AD was observed, either in the individual samples or in the combined analyses of more than 8100 subjects. Based on these negative data, it is doubtful that CALHM1 represents more than a minor genetic determinant of AD risk.