Lack of association between protocadherin 11-X/Y (PCDH11X and PCDH11Y) polymorphisms and late onset Alzheimer's disease

Abstract

A recent genome-wide association study (GWA) reported a significant association between single nucleotide polymorphisms (SNPs) at the PCDH11X gene and late-onset Alzheimer's disease (LOAD). Our research was designated to replicate this association, including non previously analyzed PCDH11X and PCDH11Y SNPs. We genotyped four PCDH11X and one PCDH11Y SNPs in a total of 420 LOAD patients and 350 healthy controls from Spain. Allele and genotype frequencies did not differ between patients and controls for the five SNPs, even after correcting by gender, age, and APOE-ε4 status. Our data were in agreement with recent reports that failed to confirm the association between PCDH11X polymorphisms and LOAD, and extended the lack of association to common PCDH11Y variants.

Introduction

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Mutations in the genes encoding the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) have been associated with rare forms of early-onset familial autosomal dominant AD (1–2% of all cases of AD) (Brouwers et al., 2008). However, most of the patients have a late-onset (> 65 years) disease (LOAD). Both, acquired/environmental and genetic/inherited risk factors contribute to the risk of developing LOAD. To date, the ε4 allele at the apolipoprotein E gene (APOE-ε4) is the only gene variant that has been recognized as a risk factor for LOAD in all populations (Chartier-Harlin et al., 1994, Saunders et al., 1993) (see the AlzGene database for a complete view of the gene variants that have been associated with LOAD; www.alzgene.org).

A recent genome-wide association (GWA) study reported a significant association between a protocadherin-11 X (PCDH11X) single nucleotide polymorphism (SNP) and LOAD (Carrasquillo et al., 2009). Although with a lower significance, a different GWA study also found some evidence of an effect of the PCDH11X on LOAD-risk (Lambert et al., 2009). There are two protocadherin-11 loci located in the homologue block of chromosomes X and Y: PCDH11X in Xq21.3 and PCDH11Y in Yp11.2. They belong to the cadherin superfamily and encode cell adhesion proteins that are expressed in fetal and adult brain (Blanco et al., 2000, Yoshida and Sugano, 1999). Different transcripts from both genes have been found in different brain regions, and it has been proposed that they contribute to the establishment and maintenance of specific neuronal connections (Blanco-Arias et al., 2004, Wu and Maniatis, 1999). Thus, the association between PCDH11X/Y SNPs and LOAD was plausible considering the putative role of these loci in the brain.

Although the initial association between PCDH11X and LOAD was based on a large cohort of patients and controls, three recent reports failed to replicate this effect on LOAD-risk (Beecham et al., 2010, Lescai et al., 2010, Wu et al., 2010) (see also the AlzGene database; www.Alzgene.org). Considering these discrepancies, additional studies from different populations are necessary, and for this reason we investigated the association between LOAD and four PCDH11X and one PCDH11Y SNPs in a population from Spain.