Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, and shows evidence for additional susceptibility genes

By D. Harold, R. Abraham, P. Hollingworth, R. Sims, A. Gerrish, M. Hamshere, Jaspreet Singh Pahwa, V. Moskvina, Kimberley Dowzell, Amy J. Williams and 76 more. Nature Genetics, 2009

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We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10−157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10−9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10−8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10−10, odds ratio = 0.86; rs3851179, P = 1.3 × 10−9, odds ratio = 0.86).

Subfields: Genetics, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/28468bee229330beaed3a5d15ccf7573df4988da

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Citations in the corpus

Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. (2012, background): “Genetic susceptibility studies have recently linked single nucleotide polymorphisms in clusterin (ApoJ), a potent regulator of complement activation, and CR1 as relatively strong susceptibility genes for AD (Harold et al. 2009; Lambert et al. 2009).”
The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics (2011, background): “Other AD risk factor genes are being discovered via genome-wide association (GWA) studies”
Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade (2010, neutral): “…,112 Clusterin (apolipoprotein J) seems to regulate the toxicity and solubility of A β and might modify its clearance at the blood–brain barrier.111 CR1 might also modify A β clearance.112 PICALM might be related to AD through a role in altering synaptic vesicle cycling or APP endocytosis.111…”
Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, neutral): “, 2013), and CR1 (Lambert et al., 2009).”