Fig. 4
Genome-wide association studies (GWAS) of PAM with TSPO PET imaging follow-up. a Manhattan plot, (b) Q–Q plot, and (c) locus summary chart for inferior temporal cortex (IT) PAM, and corresponding, (d) Manhattan plot, (e) Q–Q plot, and (f) locus summary chart for midfrontal cortex (MF) PAM GWAS. Both analyses co-varied for genotype platform, age at death, sex, postmortem interval, APOE ε4 status, and top three EIGENSTRAT principal components. g Regional association plot highlighting the MF PAM genome-wide significant locus surrounding rs2997325 (p = 1.88 × 10−8, n = 225). The color of each dot represents degree of linkage disequilibrium at that SNP based on 1000 Genomes Phase 3 reference data. The combined annotation-dependent depletion (CADD) score is plotted below the regional association plot on a scale from 0 to 20, where 20 indicates a variant with highest predicted deleteriousness. The RegulomeDB score is plotted below the CADD score, and summarizes evidence for effects on regulatory elements of each plotted SNP (5 = transcription factor-binding site or DNAase peak, 6 = other motif altered, 7 = no evidence). Below the RegulomeDB plot is an eQTL plot showing –log10(p-values) for association of each plotted SNP with the expression of the mapped gene RP11-170N11.1 (LINC01361). h Strip chart showing the significant relationship between MF PAM (on y-axis as GWAS covariate-only model residuals) and rs2997325 genotype. i Whisker plot showing the means and standard deviations of [11C]-PBR28 standard uptake value ratio (SUVR) for the left entorhinal cortex in the PET imaging sample from the Indiana Memory and Aging Study (p = 0.02, r2 = 17.1, n = 27), stratified by rs2997325 genotype. Model co-varied for TSPO rs6971 genotype, APOE ε4 status, age at study entry, and sex. Tissue enrichment analyses for (j) IT and (k) MF PAM gene sets in 30 general tissue types from GTEx v7 show Bonferroni significant enrichment (two-sided) of only the MF gene set with colon, salivary gland, breast, small intestine, stomach, lung, and blood vessel tissues. Heat maps showing enrichment for all 53 tissue types in GTEx v7, including uni-directional analyses for up-regulation and down-regulation specifically can be found in Supplementary Figure 5
