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

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

doi:10.1186/s13195-023-01376-6

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

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

Neurology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	14
Journal	Alzheimer's Research and Therapy
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/s13195-023-01376-6
State	Published - Dec 2024

Keywords

Delayed recall
Expression
Genome-wide association study
Immunity
Memory
Multi-omics

ASJC Scopus subject areas

Neurology
Clinical Neurology
Cognitive Neuroscience

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10.1186/s13195-023-01376-6

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Mei, H., Simino, J., Li, L., Jiang, F., Bis, J. C., Davies, G., Hill, W. D., Xia, C., Gudnason, V., Yang, Q., Lahti, J., Smith, J. A., Kirin, M., De Jager, P., Armstrong, N. J., Ghanbari, M., Kolcic, I., Moran, C., Teumer, A., ... Mosley, T. H. (2024). Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. Alzheimer's Research and Therapy, 16(1), Article 14. https://doi.org/10.1186/s13195-023-01376-6

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 2024, 'Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance', Alzheimer's Research and Therapy, vol. 16, no. 1, 14. https://doi.org/10.1186/s13195-023-01376-6

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title = "Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance",

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.",

keywords = "Delayed recall, Expression, Genome-wide association study, Immunity, Memory, Multi-omics",

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

note = "Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = dec,

doi = "10.1186/s13195-023-01376-6",

language = "English (US)",

volume = "16",

journal = "Alzheimer's Research and Therapy",

issn = "1758-9193",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

AU - Mei, Hao

AU - Simino, Jeannette

AU - Li, Lianna

AU - Jiang, Fan

AU - Bis, Joshua C.

AU - Davies, Gail

AU - Hill, W. David

AU - Xia, Charley

AU - Gudnason, Vilmundur

AU - Yang, Qiong

AU - Lahti, Jari

AU - Smith, Jennifer A.

AU - Kirin, Mirna

AU - De Jager, Philip

AU - Armstrong, Nicola J.

AU - Ghanbari, Mohsen

AU - Kolcic, Ivana

AU - Moran, Christopher

AU - Teumer, Alexander

AU - Sargurupremraj, Murali

AU - Mahmud, Shamsed

AU - Fornage, Myriam

AU - Zhao, Wei

AU - Satizabal, Claudia L.

AU - Polasek, Ozren

AU - Räikkönen, Katri

AU - Liewald, David C.

AU - Homuth, Georg

AU - Callisaya, Michele

AU - Mather, Karen A.

AU - Windham, B. Gwen

AU - Zemunik, Tatijana

AU - Palotie, Aarno

AU - Pattie, Alison

AU - van der Auwera, Sandra

AU - Thalamuthu, Anbupalam

AU - Knopman, David S.

AU - Rudan, Igor

AU - Starr, John M.

AU - Wittfeld, Katharina

AU - Kochan, Nicole A.

AU - Griswold, Michael E.

AU - Vitart, Veronique

AU - Brodaty, Henry

AU - Gottesman, Rebecca

AU - Cox, Simon R.

AU - Psaty, Bruce M.

AU - Boerwinkle, Eric

AU - Chasman, Daniel I.

AU - Grodstein, Francine

AU - Sachdev, Perminder S.

AU - Srikanth, Velandai

AU - Hayward, Caroline

AU - Wilson, James F.

AU - Eriksson, Johan G.

AU - Kardia, Sharon L.R.

AU - Grabe, Hans J.

AU - Bennett, David A.

AU - Ikram, M. Arfan

AU - Deary, Ian J.

AU - van Duijn, Cornelia M.

AU - Launer, Lenore

AU - Fitzpatrick, Annette L.

AU - Seshadri, Sudha

AU - Bressler, Jan

AU - Debette, Stephanie

AU - Mosley, Thomas H.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

KW - Delayed recall

KW - Expression

KW - Genome-wide association study

KW - Immunity

KW - Memory

KW - Multi-omics

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UR - http://www.scopus.com/inward/citedby.url?scp=85182631503&partnerID=8YFLogxK

U2 - 10.1186/s13195-023-01376-6

DO - 10.1186/s13195-023-01376-6

M3 - Article

C2 - 38245754

AN - SCOPUS:85182631503

SN - 1758-9193

VL - 16

JO - Alzheimer's Research and Therapy

JF - Alzheimer's Research and Therapy

IS - 1

M1 - 14

ER -

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

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