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Abstract
Late onset Alzheimer's disease (AD) is a multifactorial disorder, with AD risk influenced by both environmental and genetic factors. Recent genome-wide association studies (GWAS) have identified genetic loci associated with increased risk of developing AD. The MS4A (membrane-spanning 4-domains subfamily A) gene cluster is one of the most significant loci associated with AD risk, and MS4A6A expression is correlated with AD pathology. We identified a single nucleotide polymorphism, rs667897, at the MS4A locus that creates an antioxidant response element and links MS4A6A expression to the stress responsive Cap-n-Collar (CNC) transcription factors NRF1 (encoded by NFE2L1) and NRF2 (encoded by NFE2L2). The risk allele of rs667897 generates a strong CNC binding sequence that is activated by proteostatic stress in an NRF1-dependent manner, and is associated with increased expression of the gene MS4A6A. Together, these findings suggest that the cytoprotective CNC regulatory network aberrantly activates MS4A6A expression and increases AD risk in a subset of the population.
Highlights
Late-onset Alzheimer's disease (AD), which accounts for greater than 95% of all AD cases, has a complex multifactorial etiology
To identify putative cis-regulatory SNP (cis-SNP) contributing to differential expression of MS4A6A, we focused on variants in strong linkage disequilibrium (LD) (r2 > 0.8) with rs610932 based on data from the 1000 Genomes Project [30]
We focused on European (EUR) and East Asian (EAS) populations because rs610932 is associated with AD in both populations [8,19,20,21]
Summary
Late-onset Alzheimer's disease (AD), which accounts for greater than 95% of all AD cases, has a complex multifactorial etiology. Neuroinflammation, proteostatic stress, oxidative stress, and mitochondrial dysfunction are all likely contributors to AD progression [1,2,3,4,5]. The various cellular stressors driving neurodegeneration in AD can be modified by genetic factors, and AD has a significant but complex heritable component [5,6]. Recent genome-wide association studies (GWAS) have shed light on the genetic contributors to AD, identifying almost two-dozen loci associated with AD risk [7,8,9]. Because GWAS hits provide a window into the regulatory networks affecting disease risk, these variants represent high priority candidates for dissecting the molecular basis of AD
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