Brief communicationAssociation of CLU and PICALM variants with Alzheimer's disease
Introduction
The genetics of late-onset Alzheimer's disease (LOAD) is complex with the possible involvement of several genes. Although APOE has emerged as the strongest susceptibility marker for LOAD, it accounts for < 30% of the disease risk (Slooter et al., 1998). To identify the remaining genes for LOAD, efforts have been focused on conducting genome-wide association (GWA) studies (Abraham et al., 2008, Beecham et al., 2009, Bertram et al., 2008, Carrasquillo et al., 2009, Coon et al., 2007, Grupe et al., 2007, Li et al., 2008, Reiman et al., 2007). However, with the exception of the APOE region, no other significant associations were replicated across these GWA studies. This highlights the difficulties in identifying the remaining LOAD genes which are thought to make a relatively small contribution to the overall risk of disease and they can only be discovered using well powered case-control samples. Two recent large GWA studies have identified significant association of LOAD with SNPs in the clusterin (CLU, also known as APOJ), complement component receptor 1 (CR1) and phosphatidylinositol-binding clathrin assembly protein (PICALM) genes (Harold et al., 2009, Lambert et al., 2009). We set out to replicate these findings in a relatively large case-control sample of 2707 individuals from a single geographical location in Western Pennsylvania.
Section snippets
Methods
Late-onset Alzheimer's disease (AD) cases were Caucasian Americans (n = 1348; mean age-at-onset [AAO] 72.6 ± 6.4 years; 65.6% women; 22.8% autopsy confirmed) recruited by the University of Pittsburgh Alzheimer's Disease Research Center, all of whom met National Institute of Neurological and Communication Disorders and Stroke (NINCDS) and Alzheimer's Disease and Related Disorders Association (ADRDA) criteria for probable or definite AD. Controls were nondemented Caucasian Americans, age 60 or
Results
As expected, the presence of APOE* 4 was associated with LOAD risk (OR = 4.41; 95% confidence interval 4.05–4.80). We examined a total of 7 SNPs (3 in CLU, 2 each in CR1 and PICALM genes) most significantly implicated by either 1 or both GWA studies (Table 1). All SNPs were in Hardy-Weinberg equilibrium in both cases and controls, except for rs2279590 in CLU that deviated slightly from Hardy-Weinberg equilibrium in LOAD cases (p = 0.034). Population stratification analysis by principle
Disclosure statement
None of the authors has any actual or potential conflicts of interest that could inappropriately influence this work.
This study was approved by the University of Pittsburgh Institutional Review Board.
Acknowledgements
This study was supported by US National Institute on Aging grants AG030653, AG005133, and AG023651. We thank Dr. Jean-Charles Lambert for providing the actual genotyping counts from his study for our meta-analysis.
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