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.
Bibliographical noteFunding Information:
This work was supported by funding from the National Institute of General Medical Sciences ( R35-GM-119553 to M.S.) and the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health [ Z01-ES-100475 and Z01-ES-46008 (D.A.B)].
The LDproxy tool within the LDlink suite  was used to identify SNPs in linkage disequilibrium (LD) with rs610932; all analyses were based on data from Phase 3 of the 1000 Genomes Project  . SNPs in LD with rs610932 were then filtered using RegulomeDB  to identify polymorphisms most likely to disrupt transcription factor binding sites; SNPs with a RegulomeDB score of 1a, 1b, 2a, or 2b were considered putative cis-regulatory SNPs. Clustered DNase hypersensitive sites used in Fig. 1 , based on data from the ENCODE project  , were downloaded from the UCSC Genome browser at http://hgdownload.cse.ucsc.edu/goldenPath/hg19/encodeDCC/wgEncodeRegDnaseClustered/ (file name: wgEncodeRegDnaseClusteredV3.bed.gz). Processed genotype versus MS4A6A expression data ( Fig. 1 C and Fig. S1A) were obtained from the GTEx Portal (V6 data; https://www.gtexportal.org/home/ )  . The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.
© 2017 The Authors