These results and the association of genetic variants in GLIS3, implicated in diabetes, with CSF tau levels support previous data suggesting that diabetes
could influence risk for AD. We have previously shown that using CSF tau and ptau levels as endophenotypes it is possible to identify genetic variants implicated in AD (Kauwe et al., 2008, 2010, 2011; Cruchaga et al., 2011, 2012). This study represents the largest GWAS for CSF tau and ptau levels performed to date. Two other GWAS using the ADNI data (n = 394) have been reported previously. In these smaller studies only the APOE locus showed genome-wide significant association with CSF Aβ42 and tau levels. By using a threefold larger sample size than these studies we were drug discovery able to identify four independent genome-wide significant loci, including APOE ( Table 2). We calculated that common variants tagged by SNPs on the GWAS chip explain 6.45% and 15.14% of the overall variability in CSF ptau and tau levels, respectively. The four genome-wide significant loci identified in this
study explain 1.45% of CSF ptau and 1.28% of CSF tau variability ( Table 3). Together these four loci explain 22% and 9% of the genetic component for CSF ptau and tau levels, respectively, indicating additional variants and genes associated with CSF tau ATM/ATR targets and ptau levels may be identified in future, using larger data sets and different approaches such as whole-genome sequencing. A single-stage GWAS, rather than a two stage GWAS approach using the largest series as the discovery series, with follow up of the most significant SNPs in the rest of the samples, was used to maximize power (Dubé et al., 2007; Rohlfs et al., 2007; Kraft and Cox, 2008). There are several indications that the identified genome-wide significant loci are real signals and not artifacts from the analysis or type I errors. First, several SNPs in each locus show highly significant p values (Figure 1), and at least one SNP in each locus was directly genotyped (Table 2), eliminating the possibility that the signal is the result of an imputation error. Second, each of the genome-wide significant loci
is the result of a strong and consistent association in each data set. This is especially important, because a Liothyronine Sodium priori, the absolute values for the CSF biomarker traits are significantly different between series, which could lead to the identification of false positives. The fact that the SNPs show similar effect sizes and the same direction of effect in each data set indicates that we were able to correct for any potential series-bias and represents an internal replication of each of the associations. If we had performed a two-stage analysis we would have identified these same four loci. Finally, for three (chr. 19, APOE and 3q28 and 6p21.1) of the four genome-wide significant loci we also found that the SNPs associated with CSF levels are also associated with risk for disease, tau pathology, and/or cognitive decline.