Bioinformatic analyses indicate that the most significant SNP in this locus and 33 SNPs in linkage disequilibrium (LD) with rs9877502 are located in transcription factor binding sites and some of these SNPs are also part of a transcription factor matrix, suggesting that rs9877502 or a linked variant could influence the expression of one or more of the genes

located in this region. Rs514716, located at 9p24.2 in an intron of GLIS3, shows genome-wide significant association with both CSF tau and ptau levels ( Figure 2). The minor allele G (MAF = 0.136) is associated with lower CSF tau (β = −0.071; p = 1.07 × 10−8) and ptau levels (β = −0.072; p = 3.22 × 10−9). Seven additional Cell Cycle inhibitor intronic SNPs show genome-wide significant association with CSF ptau levels or p values lower than 9.00 × 10−05 for CSF tau levels (additional information on https://hopecenter.wustl.edu/data/Cruchaga_Neuron_2013). We used the HapMap and the 1,000 genome project data to identify all of the SNPs in linkage disequilibrium (LD, R2 > 0.8) with rs514716. A total of nine SNPs were identified, Roxadustat molecular weight all of them intronic. Our bioinformatic analysis indicated that none of these SNPs disrupt a core splice site, but all of them are located in a conserved region. Finally, for CSF ptau levels,

several, relatively rare SNPs (MAF = 0.06), located at 6p21.1, within the TREM gene cluster show genome-wide significant p values ( Figure 2). As in the case of the other genome-wide signals, at least one SNP in the region was directly genotyped (rs6922617, β = −0.094; p = 3.58 × 10−8; Table 2), and all of the CSF series contributed to the association ( Table S5). In this region, there was an additional peak driven by rs6916710 (MAF = 0.39; p = 1.58 × 10-4; β = −0.034) located in intron 2 of TREML2. In a recent study, we found a rare functional variant (R47H, rs75932628) in TREM2, which substantially increases risk for AD ( Guerreiro et al., 2012). Based on these results, we genotyped rs75932628 in the Knight-ADRC and ADNI series to test whether this variant is associated PDK4 with

CSF levels. TREM2 R47H (rs75932628) showed strong association with both CSF tau (MAF = 0.01; p = 6.9 × 10-4; β = 0.19) and ptau levels (p = 2.6 × 10-3; β = 0.16). As expected the minor allele (T) of rs75932628 is associated with higher CSF tau and ptau levels. The effect size (β) for the R47H variant was twice that of rs6922617 and rs6916710 ( Table 5), while the less significant p value is explained by the lower MAF, and sample size. To determine whether the associations seen with these three SNPs represent one signal or several independent associations we analyzed the linkage disequilibrium between the SNPs and performed conditional analyses. When rs6922617, rs6916710, or rs75932628 were included as a covariate in the model the other SNPs remained significant ( Table 5).