wustl.edu/data/Cruchaga_Neuron_2013). Together these results suggest that these three SNPs are tagging three independent signals within the TREM gene cluster that influence CSF ptau levels, and at least in the case of TREM2-R47H, AD risk. Conditional analysis was also performed for the other genome-wide significant loci to test whether the association signal at each locus is driven by a single effect or by multiple independent effects and to determine whether

the identified loci interact with each other. For the other loci, the signal for the conditioned SNP (and other SNPs in the same locus) totally disappeared confirming that the association at each locus represents a single signal. Conditioning on the genome-wide significant SNPs did not dramatically change the signals in other parts of the genome (additional information on https://hopecenter.wustl.edu/data/Cruchaga_Neuron_2013), selleckchem suggesting that there is not strong interaction between these loci and

the rest of the genome. To evaluate the specificity of these genome-wide significant loci we also examined whether the SNPs were associated with another AD biomarker, CSF Aβ42 levels. Only SNPs within the APOE region showed genome-wide association with CSF tau and CSF Aβ42 (rs2075650 p = 1.83 × 10−40). For the other regions, the p values for association with CSF Aß42 were modest: 0.02 for rs9877502, 0.03, for rs514716, and for 3.6 × 10−3 rs6922617. Furthermore, the correlation between the variants that give p values < 10−4 for either phenotype was low (r2 = Rucaparib cost Thiamine-diphosphate kinase 0.07). Together these results confirm the specificity of our results and that CSF tau/ptau and CSF Aß42 can be used as endophenotypes to identify genetic variants that influence different facets of the AD phenotype. To further characterize these associations we evaluated gene expression levels in three different ways. First, we determined whether the expression

levels of the identified genes are associated with case-control status. Second, we determined whether the SNPs associated with CSF tau/ptau levels also affect tau (MAPT) gene expression levels in brain; and third, we tested whether the SNPs were associated with expression levels of the candidate genes within each locus. To do this, we analyzed MAPT, GEMC1, IL1RAP, OSTN, and FOXP4 gene expression using cDNA from the frontal lobes of 82 AD cases and 39 nondemented individuals obtained through the Knight-ADRC Neuropathology Core. In addition, MAPT, RFX3, SLC1A1, and PPAPDC2 gene expression were analyzed using publically available data from 486 late onset Alzheimer’s disease cases and 279 neuropathologically clean individuals form the GSE15222 data set ( Myers et al., 2007). We found strong association for RFX3 (p = 1.39 × 10−9; β = 0.42), SLC1A1 (p = 1.01 × 10−4; β = −0.28), and PPAPDC2 (p = 4.80 × 10−3; β = −0.35), all located in the chromosome 9 region of association, with case-control status.