Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease
Open accessPreprint — published as 10.1371/journal.pone.0218111
Abstract
A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimer’s Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates. Three novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423 . The ZNF423 gene resides in an Alzheimer’s disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.
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Several genome-wide significant loci not previously detected at the SNP level have been identified using gene-based approaches, including those assigned to TP53INP and PPARGC1A.
“Several genome-wide significant loci not previously detected at the SNP level have been identified using gene-based approaches, including those assigned to TP53INP [115] and PPARGC1A [116].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [116]
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ARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · see citing works
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Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
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- Authors
- Baker, E., Sims, R., Leonenko, G., Frizzati, A., Harwood, J., Grozeva, D., GERAD/PERADES, consortia, I., Morgan, K., Passmore, P., Holmes, C., Powell, J., Brayne, C., Gill, M., Mead, S., Heun, R., Bossù, P., Spalletta, G., Goate, A., Cruchaga, C., van Duijn, C., Maier, W., Ramirez, A., Jones, L., Hardy, J., Ivanov, D., Hill, M., Holmans, P., Allen, N., Morgan, P., Williams, J., Escott-Price, V., GERAD Consortium, ADGC Consortium, CHARGE Consortium, & EADI Consortium
- Affiliations
- Cardiff University (GB)
- University of Nottingham (GB)
- University of Cambridge (GB)
- Queen's University Belfast (GB)
- Fondazione Santa Lucia (IT)
- King's College London (GB)
- Washington University in St. Louis (US)
- German Center for Neurodegenerative Diseases (DE)
- University of Bonn (DE)
- University of Cologne (DE)
- Heidelberg University (DE)
- UCL Queen Square Institute of Neurology (GB)
- Boston University (US)
- Inserm (FR)
- Corresponding author
- Williams, Julie
- ORCID
- Sims, Rebecca
- Leonenko, Ganna
- Harwood, Janet
- Grozeva, Detelina
- Morgan, Kevin
- Passmore, Peter
- Holmes, Clive
- Powell, John
- Brayne, Carol
- Gill, Michael
- Mead, Simon
- Bossù, Paola
- Spalletta, Gianfranco
- Goate, Alison
- Cruchaga, Carlos
- Maier, Wolfgang
- Jones, Lesley
- Hardy, John
- Ivanov, Dobril
- Hill, Matthew
- Holmans, Peter
- Allen, Nicholas
- Williams, Julie
- Venue
- PLoS ONE
- Publisher
- openRxiv
- Published
- 2018-07-23
- Volume
- 14
- Issue
- 7
- Pages
- e0218111-e0218111
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC6613773
- OpenAlex
- W2958689915
- Cited by
- 31
- References
- 1
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 3
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- PLoS ONE (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
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- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Repository@Nottingham (University of Nottingham) (publishedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
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- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, other-oa)
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- DZNE Pub (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo
- Apollo (cc-by)
- Funders
- University of Miami
- University of Pennsylvania
- Northwestern University
- School of Medicine, Boston University
- University of Washington
- Johns Hopkins University
- University of Pittsburgh
- Rush University
- Wellcome Trust (MR/L010305/1)
- National Institute for Health and Care Research (NF-SI-0616-10090, NF-SI-0617-10175, NF-SI-0611-10084)
- Parkinson's UK (G-1307)
- Rosetrees Trust
- Agence Nationale de la Recherche (ANR-11-LABX-0009)
- UK Dementia Research Institute
- Dementias Platform UK (MR/L023784/2, MR/L010305/1)
- University of California, Los Angeles
- Perelman School of Medicine, University of Pennsylvania
- Geriatric Research Education and Clinical Center
- Medical Research Council (MR/L023784/2, MR/K01417X/1, MR/L501517/1, MR/L501542/1, MR/J004758/1, UKDRIdata023, MR/L010305/1, MC_PC_17112, MR/K013041/1, MR/M009076/1, MR/L023784/1)
- National Institute on Aging (P30AG010129, U01AG049505, U01AG052409, R01AG054076, U01AG032984, U24AG056270, U24AG021886)
- National Institute of Neurological Disorders and Stroke (R01NS017950)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- late-onset Alzheimer's disease, genetic susceptibility loci, gene-based association analysis, PGC-1α, RORA, ZNF423, circadian rhythm, energy metabolism, amyloid plaques, single nucleotide polymorphisms, genotype imputation
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Alzheimer Disease, Cholesterol, Circadian Rhythm, DNA Damage, DNA Repair, Energy Metabolism, Female, Humans, Inflammation, Male, Proteins, Genome, Human, Amyloid beta-Peptides, Centrosome, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Nuclear Receptor Subfamily 1, Group F, Member 1
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