Intermediate phenotypes identify divergent pathways to Alzheimer's disease

Autor: Lori B. Chibnik, Philip L. De Jager, Joshua M. Shulman, Julie A. Schneider, David A. Bennett, Cristin Aubin
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Male
Candidate gene
Neurogenetics
lcsh:Medicine
Single-nucleotide polymorphism
Genome-wide association study
Plaque
Amyloid
Neuropathology
Biology
Genetics and Genomics/Complex Traits
Polymorphism
Single Nucleotide
03 medical and health sciences
0302 clinical medicine
Cognition
Alzheimer Disease
medicine
Neurites
SNP
Humans
Genetic Predisposition to Disease
Cognitive decline
lcsh:Science
Genetics and Genomics/Genetics of Disease
030304 developmental biology
Genetics
Aged
80 and over
0303 health sciences
Multidisciplinary
lcsh:R
medicine.disease
Phenotype
Neurological Disorders/Neurogenetics
Genetic Loci
Pathology/Neuropathology
Neurofibrils
Female
lcsh:Q
Alzheimer's disease
Neurological Disorders/Alzheimer Disease
030217 neurology & neurosurgery
Research Article
Genome-Wide Association Study
Zdroj: PLoS ONE, Vol 5, Iss 6, p e11244 (2010)
PLoS ONE
ISSN: 1932-6203
Popis: Background Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden. Methods/Principal Findings Thirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p = 0.009) and global cognition (p = 0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p = 3.57×10−4). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts. Conclusions/Significance The findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder.
Databáze: OpenAIRE
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