Genetic variation in PCDH11X is associated with susceptibility to late onset alzheimer's disease

Minerva M. Carrasquillo, Fanggeng Zou, V. Shane Pankratz, Samantha L. Wilcox, Li Ma, Louise P. Walker, Curtis S. Younkin, Linda H. Younkin, Gina D. Bisceglio, Nilufer Ertekin-Taner, Julia E. Crook, Dennis W. Dickson, Ronald C. Petersen, Neill R. Graff-Radford, Steven G. Younkin

Research output: Contribution to journalArticlepeer-review


By analyzing late onset Alzheimer's disease (LOAD) in a genome wide association study of 3 American Caucasian series and evaluating the 25 SNPs with most significant allelic association in 4 additional series, we identified a SNP (rs5984894) on Xq21.3 in PCDHUX 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 a global p value of 3.9 × 10-12 in the combined series. Odds ratios were 1.75 (95% CI 1.42-2.16) for female homozygotes (P=2.0xl0-7) and 1.26 (95% CI 1.05-1.51) for female heterozygotes (P=0.01) compared to female non-carriers. For male hemizygotes (P,=0.07) compared to male non-carriers the odds ratio was 1.18 (95% CI 0.99-1.41). The effect of this variant was dose dependent, as females homozygotes for the minor allele were at significantly greater risk than heterozygous females and hemizygous males. We tested additional variants in PCDHUX for association with LOAD. One of these variants, rs2573905, showed association with LOAD similar to that for rs5984894, albeit with a slightly more significant p-value (5.4xl0-13). This is not surprising since these two variants are in near perfect linkage 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 lOObp, suggesting a possible functional role for this SNP. Joint analysis of APOE and rs2573905 genotypes showed that 75 women with LOAD (4.9%) were homozygous both for APOE e4 and for rs2573905 whereas only 2 unaffected women (0.15%), both age 73, were double homozygotes. These finding suggest that the double 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.

Original languageEnglish (US)
Pages (from-to)S125-S134
JournalHirosaki Medical Journal
Issue numberSUPPL.
StatePublished - Jul 8 2010

ASJC Scopus subject areas

  • General Medicine


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