Based on the results of these bioinformatic analyses we performed several gene-expression experiments. IL1RAP showed a nominally significant association with case-control status (p = 0.04). In addition rs9877502 showed a significant association with IL1RAP expression in frontal cortex

(p = 0.02; Table S5). The lack of association selleck screening library with risk for AD in the ADGC GWAS for the most significant SNP in the 6p21.1 locus may reflect insufficient power because the SNP has a low minor allele frequency (MAF = 0.06). This hypothesis is supported by our recent identification of a rare functional coding variant (TREM2- R47H, rs75932628) in the same locus which substantially increases risk for AD ( Guerreiro et al., 2012), and is also associated with CSF ptau levels in the present study. Interestingly, the genome-wide significant signal (tagged by rs6922617) is not in LD with rs75932628. Conditional analyses in this region identified another independent SNP ( Figure 2; Table 5), located in an intron of TREML2 that is associated with CSF tau and ptau levels. These data suggest that in this region there are at least three

independent signals modifying CSF tau levels and risk for AD. Six TREM-family genes (TREM1, TREM2, and TREML1 to TREML4) are located in this region suggesting that several variants in genes with similar function may affect risk for AD in an independent manner. The genome-wide significant SNP in this locus (rs11966476; Bioactive Compound Library p = 4.79 × 10−8), is located in a regulatory element and could modify the expression of FOXP4, TREML3, TREML4, or TREM1 ( Figure 2). Unfortunately, these genes were not included in the GSE15222 data set and Taqman assays for these genes were out of the dynamic range so we were unsuccessful in analyzing expression levels in brain tissue. Despite this, data from the Allen Brain Atlas suggests that these genes are expressed in the brain. TREM2 was Edoxaban expressed at higher levels in brain tissue from AD cases compared to controls (p = 1.35 × 10−5), as predicted in our previous studies ( Guerreiro et al., 2012). For

the 9p24.2 locus, we did not observe significant association with risk for AD. This could be because these SNPs affect another aspect of AD such as disease duration or age at onset. Alternatively, these SNPs could affect CSF clearance or protein half-life without affecting risk for AD. If this were the case, we would expect that the same locus would be associated with levels of other CSF proteins. To test this, we looked at the association of all of the SNPs identified in this study at the genome-wide significance level with other CSF biomarkers. We did not observe association between these SNPs and CSF levels of either APOE or Aβ (Cruchaga et al., 2012), suggesting that these loci are specific for CSF tau levels and are not associated with CSF clearance or protein half life in general.