Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.

TitleMulti-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.
Publication TypeJournal Article
Year of Publication2024
AuthorsMei, H, Simino, J, Li, L, Jiang, F, Bis, JC, Davies, G, W Hill, D, 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, B Windham, G, 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, M Ikram, A, Deary, IJ, van Duijn, CM, Launer, L, Fitzpatrick, AL, Seshadri, S, Bressler, J, Debette, S, Mosley, TH
JournalAlzheimers Res Ther
Volume16
Issue1
Pagination14
Date Published2024 Jan 20
ISSN1758-9193
KeywordsAged, Cognition, Genome-Wide Association Study, Humans, Memory, MicroRNAs, Multiomics, Polymorphism, Single Nucleotide
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.

DOI10.1186/s13195-023-01376-6
Alternate JournalAlzheimers Res Ther
PubMed ID38245754
PubMed Central IDPMC10799499
Grant ListR01 HL103612 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
P01 DK070756 / DK / NIDDK NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 HL034594 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
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R01 NS017950 / NS / NINDS NIH HHS / United States
U01 HG004728 / HG / NHGRI NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
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UL1 RR025005 / RR / NCRR NIH HHS / United States
K08 AG034290 / AG / NIA NIH HHS / United States
1P20GM144041 / GM / NIGMS NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
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R01 CA067262 / CA / NCI NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
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HHSN268200800007C / HL / NHLBI NIH HHS / United States
P20 GM144041 / GM / NIGMS NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U01 CA067262 / CA / NCI NIH HHS / United States
R01 CA065725 / CA / NCI NIH HHS / United States
U01 HL054464 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01HL105756 / NH / NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
HHSN268201700002C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01 HL054457 / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
R01 EY015473 / EY / NEI NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
U01 CA098233 / CA / NCI NIH HHS / United States
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MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom
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R01 AG020098 / AG / NIA NIH HHS / United States
HHSN268201700005C / HL / NHLBI NIH HHS / United States
HHSN268201700001C / HL / NHLBI NIH HHS / United States
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N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201700003C / HL / NHLBI NIH HHS / United States
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N01HC25195 / HL / NHLBI NIH HHS / United States
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R01 CA049449 / CA / NCI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
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U01 CA049449 / CA / NCI NIH HHS / United States
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