Kristina Tacey

Association of ABCA1 with late-onset Alzheimer's disease is not observed in a case-control study.

Genetic association of ABCA1 or the ATP-binding cassette A1 transporter with late-onset Alzheimers disease (LOAD) has recently been proposed for a haplotype comprised of three single nucleotide polymorphisms (SNPs). We have genotyped these and other ABCA1 SNPs in a LOAD case-control series of 796 individuals (419 cases versus 377 controls) collected at Washington University. While our sample series is larger and thus presumably has greater power than any of the series used to implicate ABCA1, we were unable to replicate the published association, using either single markers or multiple marker haplotypes. Further, we did not observe significant and replicated association of other ABCA1 SNPs we examined with the disease, thus these ABCA1 variants do not appear to influence the risk of LOAD in this study.

A Case-Control Association Study of the 12 Single-Nucleotide Polymorphisms Implicated in Parkinson Disease by a Recent Genome Scan

To the Editor: To validate associations of SNPs that Maraganore et al.1 reported as associated with Parkinson disease (PD [MIM 168600]), we constructed a case-control series from PD cases and matched population/convenience controls that are available through the National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resources at the Coriell Institute. Cases met United Kingdom Brain Bank criteria for idiopathic PD,2 and controls were neurologically normal. This series comprises 311 pairs of age- and sex-matched cases and controls. Cases had an age at disease onset ranging from 50 to 87 years (average [±SD] 63.8 ± 8.9 years) and were sampled at the age of 52–92 years (average [±SD] 70.1 ± 8.5 years). Controls were also sampled at the age of 52–92 years (average [±SD] 70.2 ± 8.5 years). All cases and controls are white, and each group includes 165 females (53.1%) and 146 males (46.9%), respectively. Cases in this series do not carry the Gly2019Ser mutation in LRRK2 [MIM 609007], which may occur in idiopathic PD,3 and several tests did not reveal evidence of significant population stratification for 78 individually genotyped null markers (data not shown). We individually genotyped the 11 SNPs that were reported significant and one of the two SNPs that map to the PARK10 [MIM 606852] locus (the two reported-significant SNPs are highly correlated: r2=0.99), using allele-specific real-time PCR in our PD case-control sample set. Cases and controls were run on the same plate in a blinded fashion. Our genotyping method has an overall accuracy of >99%.4 As an additional indication of genotyping quality, we calculated deviation from Hardy-Weinberg equilibrium (HWE) in cases and controls. One marker had an HWE exact P value of <.05 (.017 for rs2245218 in cases), but further examination of our genotype data did not reveal questionable calls. Therefore, these data were included in our analysis. All SNPs were tested for allelic association with PD with the use of χ2 statistics to calculate two-sided P values (table 1). Power calculations were done for a sample size of 311 pairs for each SNP, with the use of a one-sided allelic χ2-hypothesis test at a significance level of 0.05 and with the assumption that the control-allele frequencies of the unrelated controls and odds ratios (ORs) in table 4 in Maraganore et al.1 are true population parameters. Power calculation for rs7520966 was based on the tier 2 OR given in the text of Maraganore et al.,1 since it did not appear in their table 4. Table 1 Allelic Tests of SNPs Associated with Late-Onset PD Two markers, rs10200894 and rs17329669, were replicated in our sample set at P 50 years, whereas the study by Maraganore et al. included both early- and late-onset cases.1 Thus, it is possible that nonreplicated markers are associated with early-onset PD but make a lesser contribution to the more common, late-onset form of the disease. Additional studies are required to further assess the association of these markers with PD.

Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme.

Linkage studies have suggested there is a susceptibility gene for late onset Alzheimers disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin‐degrading enzyme (IDE), a protease involved in the catabolism of Aβ. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three “tagging” SNPs identified in an earlier study. We used four case‐control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P‐value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over‐represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.

Alpha-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer's disease.

The gene encoding α-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer’s disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that α-T-catenin is expressed in human brain, and like other α-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Aβ deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n>700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.

The BDNF val66met polymorphism is not associated with late onset Alzheimer's disease in three case–control samples

The BDNF val66met polymorphism is not associated with late onset Alzheimers disease in three case–control samples

O2-02-07: Genetic variants on chromosome 9 are associated with late-onset Alzheimer’s disease, variation in allele-specific gene expression, and differential apoptotic response

Yonghong Li, Andrew Grupe, Charles Rowland, Petra Nowotny, John S.K. Kauwe, Scott Smemo, Anthony Hinrichs, Kristina Tacey, Shirley Kwok, Joseph Catanese, John Sninsky, Thomas J. White, Paul Hollingworth, Sandra L. Harris, Arnold Levine, Fabienne Wavrant-De Vrieze, John Hardy, Michael O’Donovan, Simon Lovestone, John Morris, Leon J. Thal, Michael Owen, Julie Williams, Alison Goate, Celera Diagnostics, Alameda, CA, USA; Washington University, St. Louis, MO, USA; Cardiff University, Cardiff, United Kingdom; Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Institute for Advanced Study, Princeton, NJ, USA; National Institute on Aging, Bethesda, MD, USA; Institute of Psychiatry, London, United Kingdom; University of California, San Diego, San Diego, CA, USA. Contact e-mail: yonghong.li@celeradiagnostics.com