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

Abstract

By analyzing late-onset Alzheimer's disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases and 1,255 controls) and evaluating the 25 SNPs with the most significant allelic association in four additional series (1,547 cases and 1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in individuals of European descent from the United States. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.7 x 10(-5) in stage 1, 4.8 x 10(-6) in stage 2 and 3.9 x 10(-12) in the combined data. Odds ratios were 1.75 (95% CI = 1.42-2.16) for female homozygotes (P = 2.0 x 10(-7)) and 1.26 (95% CI = 1.05-1.51) for female heterozygotes (P = 0.01) compared to female noncarriers. For male hemizygotes (P = 0.07) compared to male noncarriers, the odds ratio was 1.18 (95% CI = 0.99-1.41).

Figure 1

Schematic overview of PCDH11X and LD plot showing PCDH11X haplotype blocks. Unadjusted allelic association P values from stage I for variants encompassing the PCDH11X locus are plotted over physical distance above the PCDH11X gene diagram. The four PCDH11X RefSeq isoforms and their chromosomal positions are depicted as in Entrez Gene (build 36.3). The LD plot shown is for variants in the PCDH11X locus (stage I data in Haploview 4.0, solid spine haplotype block definition, r² values with D'color scheme).