Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance
Authors: Mei Hao , Simino Jeannette , Li Lianna , Jiang Fan , Bis Joshua C. , Davies Gail , Hill W David , Xia Charley , Gudnason Vilmundur , Yang Qiong , Lahti Jari , Smith Jennifer A. , Kirin Mirna , De Jager Philip , Armstrong Nicola J. , Ghanbari Mohsen , Kolcic Ivana , Moran Christopher , Teumer Alexander , Sargurupremraj Murali , Mahmud Shamsed , Fornage Myriam , Zhao Wei , Satizabal Claudia L. , Polasek Ozren , Räikkönen Katri , Liewald David C. , Homuth Georg , Callisaya Michele , Mather Karen A. , Windham B. Gwen , Zemunik Tatijana , Palotie Aarno , Pattie Alison , van der Auwera Sandra , Thalamuthu Anbupalam , Knopman David S. , Rudan Igor , Starr John M. , Wittfeld Katharina , Kochan Nicole A. , Griswold Michael E. , Vitart Veronique , Brodaty Henry , Gottesman Rebecca , Cox Simon R. , Psaty Bruce M. , Boerwinkle Eric , Chasman Daniel I. , Grodstein Francine , Sachdev Perminder S. , Srikanth Velandai , Hayward Caroline , Wilson James F. , Eriksson Johan G. , Kardia Sharon L. R. , Grabe Hans J. , Bennett David A. , Ikram M. Arfan , Deary Ian J. , van Duijn Cornelia M. , Launer Lenore , Fitzpatrick Annette L. , Seshadri Sudha , Bressler Jan , Debette Stephanie , Mosley Thomas H. 
Published: January 2024

Abstract
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.