Alzheimer’s Research & Therapy (Jan 2024)
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
Affiliations
- Hao Mei
- Department of Data Science, John D. Bower School of Population Health, University of Mississippi Medical Center
- Jeannette Simino
- Department of Data Science, John D. Bower School of Population Health, University of Mississippi Medical Center
- Lianna Li
- Department of Biology, Tougaloo College
- Fan Jiang
- Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine
- Joshua C. Bis
- Department of Medicine, Cardiovascular Health Research Unit, University of Washington
- Gail Davies
- Department of Psychology, Lothian Birth Cohorts Group, University of Edinburgh
- W David Hill
- Department of Psychology, Lothian Birth Cohorts Group, University of Edinburgh
- Charley Xia
- Department of Psychology, Lothian Birth Cohorts Group, University of Edinburgh
- Vilmundur Gudnason
- Icelandic Heart Association
- Qiong Yang
- Department of Biostatistics, Boston University School of Public Health
- Jari Lahti
- Turku Institute for Advanced Research, University of Turku
- Jennifer A. Smith
- Department of Epidemiology, School of Public Health, University of Michigan
- Mirna Kirin
- Work completed while at The University of Edinburgh
- Philip De Jager
- Taub Institute for Research On Alzheimer’s Disease and the Aging Brain, Columbia Irving University Medical Center
- Nicola J. Armstrong
- Mathematics and Statistics, Curtin University
- Mohsen Ghanbari
- Department of Epidemiology, Erasmus Medical Center University Medical Center
- Ivana Kolcic
- School of Medicine, University of Split
- Christopher Moran
- Department of Geriatric Medicine, Frankston Hospital, Peninsula Health
- Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald
- Murali Sargurupremraj
- Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, University of Bordeaux
- Shamsed Mahmud
- Department of Data Science, John D. Bower School of Population Health, University of Mississippi Medical Center
- Myriam Fornage
- The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School, University of Texas Health Science Center at Houston
- Wei Zhao
- Department of Epidemiology, School of Public Health, University of Michigan
- Claudia L. Satizabal
- The University of Texas Health Science Center at San Antonio
- Ozren Polasek
- School of Medicine, University of Split
- Katri Räikkönen
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki
- David C. Liewald
- Department of Psychology, Lothian Birth Cohorts Group, University of Edinburgh
- Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald
- Michele Callisaya
- Peninsula Clinical School, Central Clinical School, Monash University
- Karen A. Mather
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- B. Gwen Windham
- Gertrude C. Ford Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center
- Tatijana Zemunik
- School of Medicine, University of Split
- Aarno Palotie
- Department of Medicine, Department of Neurology and Department of Psychiatry, Analytic and Translational Genetics Unit, Massachusetts General Hospital
- Alison Pattie
- Department of Psychology, Lothian Birth Cohorts Group, University of Edinburgh
- Sandra van der Auwera
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald
- Anbupalam Thalamuthu
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- David S. Knopman
- Department of Neurology, Mayo Clinic
- Igor Rudan
- Centre for Global Health Research, Usher Institute, University of Edinburgh
- John M. Starr
- Department of Psychology, Lothian Birth Cohorts Group, University of Edinburgh
- Katharina Wittfeld
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald
- Nicole A. Kochan
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Michael E. Griswold
- Gertrude C. Ford Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center
- Veronique Vitart
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Henry Brodaty
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Rebecca Gottesman
- Stroke, Cognition, and Neuroepidemiology (SCAN) Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Simon R. Cox
- Department of Psychology, Lothian Birth Cohorts Group, University of Edinburgh
- Bruce M. Psaty
- Department of Medicine, Cardiovascular Health Research Unit, University of Washington
- Eric Boerwinkle
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston
- Daniel I. Chasman
- Harvard Medical School
- Francine Grodstein
- Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
- Perminder S. Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales
- Velandai Srikanth
- Department of Geriatric Medicine, Frankston Hospital, Peninsula Health
- Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- James F. Wilson
- Centre for Global Health Research, Usher Institute, University of Edinburgh
- Johan G. Eriksson
- Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital
- Sharon L. R. Kardia
- Department of Epidemiology, School of Public Health, University of Michigan
- Hans J. Grabe
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald
- David A. Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center
- M. Arfan Ikram
- Department of Epidemiology, Erasmus Medical Center University Medical Center
- Ian J. Deary
- Department of Psychology, Lothian Birth Cohorts Group, University of Edinburgh
- Cornelia M. van Duijn
- Nuffield Department of Population Health, Medical Sciences Division, University of Oxford
- Lenore Launer
- Laboratory of Epidemiology and Population Sciences, National Institute On Aging
- Annette L. Fitzpatrick
- Department of Epidemiology, University of Washington
- Sudha Seshadri
- The National Heart Lung and Blood Institute’s Framingham Heart Study
- Jan Bressler
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston
- Stephanie Debette
- Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, University of Bordeaux
- Thomas H. Mosley
- Gertrude C. Ford Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center
- DOI
- https://doi.org/10.1186/s13195-023-01376-6
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 15
Abstract
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
