Genome-wide association study of the rate of cognitive decline in Alzheimer's disease

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA. Electronic address: .
Alzheimer's & dementia: the journal of the Alzheimer's Association (Impact Factor: 17.47). 03/2013; 10(1). DOI: 10.1016/j.jalz.2013.01.008
Source: PubMed

ABSTRACT BACKGROUND: Substantial interindividual variability exists in the disease trajectories of Alzheimer's disease (AD) patients. Some decline rapidly whereas others decline slowly, and there are no known explanations for this variability. We describe the first genome-wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition. METHODS: The discovery sample was 303 AD cases recruited in the Alzheimer's Disease Neuroimaging Initiative and the replication sample was 323 AD cases from the Religious Orders Study and Rush Memory and Aging Project. In the discovery sample, Alzheimer's Disease Assessment Scale-cognitive subscale responses were tested for association with genome-wide single-nucleotide polymorphism (SNP) data using linear regression. We tested the 65 most significant SNPs from the discovery sample for association in the replication sample. RESULTS: We identified SNPs in the spondin 1 gene (SPON1), the minor alleles of which were significantly associated with a slower rate of decline (rs11023139, P = 7.0 × 10(-11)) in the discovery sample. A SPON1 SNP 5.5 kb upstream was associated with decline in the replication sample (rs11606345, P = .002). CONCLUSION: SPON1 has not been previously associated with AD risk, but it is plausibly related because the gene product binds to the amyloid precursor protein and inhibits its cleavage by β-secretase. These data suggest that SPON1 may be associated with the differential rate of cognitive decline in AD.

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Available from: Lindsay Farrer, Feb 07, 2015
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    • "Fourth, the discovery of a GWAS hit—in ENIGMA or any other GWAS study—is the beginning of a long road of discovery, especially if the finding is intergenic or in a gene of unknown function. Some genomic screens of anatomical or structural connectivity data have implicated genes such as SPON1 (Jahanshad et al. 2013b) and FRMD6 (Ryles et al. 2012) that were discovered in later case–control studies to be risk genes for AD (Hong et al. 2012; Sherva et al. 2013). Functional validation of genetic variants reliably implicated in large scale studies will be the way we learn new biological processes and further our understanding of risk for psychiatric diseases. "
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