Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE

Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease (MIND), Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 11/2008; 83(5):623-32. DOI: 10.1016/j.ajhg.2008.10.008
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.

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Available from: BASAVARAJ Hooli, Sep 29, 2015
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    • "Among the genes identified as risk factors for AD were genes expressed by microglia. For example CD33 was identified as a sporadic AD risk locus [8, 50, 87]. CD33 is a transmembrane protein and a member of the sialic acid-binding immunoglobulin-like lectins (Siglecs). "
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    Acta Neuropathologica 07/2014; 128(3). DOI:10.1007/s00401-014-1321-z · 10.76 Impact Factor
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    • "Since 2007, dozens of GWAS of thousands of samples from AD patients and nondemented elderly controls have been performed, resulting in the identification of a number of new genetic loci with genome-wide significance (<5 × 10−8) [85–109]. Some of these foci have been identified in more than two GWAS and have compelling evidence supporting an association with LOAD, including clusterin (CLU) [95, 96, 99, 107], complement component receptor 1 (CR1) [95, 104–106], and phosphatidylinositol binding clathrin assembly protein (PICALM) [96, 99, 107, 108], bridging integrator 1 (BIN1) [99, 101, 104–107], sialic acid binding Ig-like lectin (CD33) [90, 105–107], CD2-associated protein (CD2AP) [105, 106], membrane spanning 4A gene cluster (MS4A6A/MS4A4E) [105–108], ephrin receptor A1 (EPHA1) [105–107], and ATP-binding cassette transporter (ABCA7) [105–107, 109]. Recently, a rare susceptibility variant (rs75932628) in the triggering receptor expressed on myeloid cells 2 (TREM2) gene was identified to be associated with LOAD [110, 111]. "
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    BioMed Research International 05/2014; 2014:291862. DOI:10.1155/2014/291862 · 3.17 Impact Factor
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    • "We chose TNF-α and IL-6 in the current studies because these two pre-inflammatory cytokines have been shown to be associated with the neuroinflammation associated with surgery under anesthesia ([6], [7], [8], [9], [11], reviewed in [10]). Finally, CD33 is a newly suggested AD associated gene [12]. Protein CD33 is a member of the SIGLEC family of lectins can bind to sialic acid and regulate the innate immune system [13]. "
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