Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.
Mei H., Simino J., Li L., Jiang F., Bis JC., Davies G., Hill WD., Xia C., Gudnason V., Yang Q., Lahti J., Smith JA., Kirin M., De Jager P., Armstrong NJ., Ghanbari M., Kolcic I., Moran C., Teumer A., Sargurupremraj M., Mahmud S., Fornage M., Zhao W., Satizabal CL., Polasek O., Räikkönen K., Liewald DC., Homuth G., Callisaya M., Mather KA., Windham BG., Zemunik T., Palotie A., Pattie A., van der Auwera S., Thalamuthu A., Knopman DS., Rudan I., Starr JM., Wittfeld K., Kochan NA., Griswold ME., Vitart V., Brodaty H., Gottesman R., Cox SR., Psaty BM., Boerwinkle E., Chasman DI., Grodstein F., Sachdev PS., Srikanth V., Hayward C., Wilson JF., Eriksson JG., Kardia SLR., Grabe HJ., Bennett DA., Ikram MA., Deary IJ., van Duijn CM., Launer L., Fitzpatrick AL., Seshadri S., Bressler J., Debette S., Mosley TH.
BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.