＜Symposium IV＞Genetic variation in PCDH11X is associated with susceptibility to late onset Alzheimer's disease

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By analyzing late onset Alzheimer’s disease （LOAD） in a genome wide association study of 3 AmericanCaucasian series and evaluating the 25 SNPs with most significant allelic association in 4 additional series, weidentifi ed a SNP （rs5984894） on Xq21.3 in PCDH11X that is strongly associated with LOAD in American Caucasians（total n=4,855; AD:2,391; control:2,464）. Analysis of rs5984894 by logistic regression using sex as a covariate gave aglobal p value of 3.9 x 10-12 in the combined series. Odds ratios were 1.75（ 95% CI 1.42-2.16） for female homozygotes（P=2.0x10-7） and 1.26 （95% CI 1.05-1.51） for female heterozygotes （P=0.01） compared to female non-carriers. Formale hemizygotes （P=0.07） compared to male non-carriers the odds ratio was 1.18 （95% CI 0.99-1.41）. The eff ectof this variant was dose dependent, as females homozygotes for the minor allele were at signifi cantly greater riskthan heterozygous females and hemizygous males. We tested additional variants in PCDH11X for association withLOAD. One of these variants, rs2573905, showed association with LOAD similar to that for rs5984894, albeit witha slightly more significant p-value （5.4x10-13）. This is not surprising since these two variants are in near perfectlinkage disequilibrium （r2 = 0.98, D’ = 0.99）, and the minor allele of these two SNPs occur on the same haplotype.However, rs2573905 is in a sequence that has been evolutionarily conserved between human and mice, with 70%sequence identity over 100bp, suggesting a possible functional role for this SNP. Joint analysis of APOE and rs2573905genotypes showed that 75 women with LOAD （4.9%） were homozygous both for APOE e4 and for rs2573905whereas only 2 unaff ected women （0.15%）, both age 73, were double homozygotes. These fi nding suggest that thedouble homozygote may be fully penetrant in women over the age of 73 and that this combination may account for~5% of the AD that occurs in women.

＜Symposium IV＞Genetic variation in PCDH11X is associated with susceptibility to late onset Alzheimer's disease

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