Year: 2013
Type: article
Study design: Observational Study
Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting approximately 5.4 million individuals in the US and is the most common cause of dementia in North America and Europe. Genetic factors play an important role in the pathogenesis of AD and contribute to the variance of age at onset (AAO). APOE4 has a strong effect on AAO and an additional 4–5 loci may contribute to the heritability of AAO. AAO is an important endophenotype and a potential therapeutic target for disease modifying therapy. Ordered subset analysis using AAO as a quantitative endophenotype may identify genetic risk that contributes to a subset of AD. This CNV association study with AAO of AD was designed to examine the role of these low-frequency variants with intermediate penetrance in relation to AAO of AD. 781 AD subjects and 200 normal controls enrolled in the Texas Alzheimer Research Consortium project were phenotyped for AAO and genotyped on the Genome-Wide Human SNP Array 6.0 (Affymetrix) array. The PCA corrected logR data was segmented to reduce the dataset to probes where any event occurred. Ordered subset analysis for the numeric array data means was performed by adding sequentially groups of subjects with the same AAO. The ordered subset analysis using the univariate segmentated logR data identified 28 probes corresponding to 6 chromosomal regions, where the maximum p-value survived multiple testing correction. When using the multivariate segmented logR data, 41 probes survived multiple testing correction. Several of the gains and losses contributed to the young AAO subset (<60), but some of the dosage differences appeared to be contributing to the older AAO (>80). The APOE4 allele had its maximum effect at around AAO 74 consistent with previous reports. Replication on the NIA-LOAD familial dataset is ongoing. The genetic heterogeneity of AD has been demonstrated in multiple GWAS studies. Ordered subset analysis using AAO as a quantitative endophenotype generates candidate genes that can be tested in case-control association studies informed by the AAO where the maximum effect is expected.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2026979958