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

Abstract

Steve Younkin and colleagues report the results of a genome-wide association study for late-onset Alzheimer's disease. A variant on the X chromosome in PCDH11X is associated with increased risk of the disorder. PCDH11X encodes a protocadherin and is a member of a cell surface receptor molecule family. 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 × 10−5 in stage 1, 4.8 × 10−6 in stage 2 and 3.9 × 10−12 in the combined data. Odds ratios were 1.75 (95% CI = 1.42–2.16) for female homozygotes (P = 2.0 × 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).