Genetically regulated expression in late-onset Alzheimer's disease implicates risk genes within known and novel loci.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
06 12 2021
06 12 2021
Historique:
received:
05
03
2021
accepted:
06
10
2021
revised:
27
09
2021
entrez:
7
12
2021
pubmed:
8
12
2021
medline:
1
2
2022
Statut:
epublish
Résumé
Late-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic mechanisms of complex diseases. Here, we conducted GReX analysis within and across 51 tissues on 39 LOAD GWAS data sets comprising 58,713 cases and controls from the Alzheimer's Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer's Project (IGAP). Meta-analysis across studies identified 216 unique significant genes, including 72 with no previously reported LOAD GWAS associations. Cross-brain-tissue and cross-GTEx models revealed eight additional genes significantly associated with LOAD. Conditional analysis of previously reported loci using established LOAD-risk variants identified eight genes reaching genome-wide significance independent of known signals. Moreover, the proportion of SNP-based heritability is highly enriched in genes identified by GReX analysis. In summary, GReX-based meta-analysis in LOAD identifies 216 genes (including 72 novel genes), illuminating the role of gene regulatory models in LOAD.
Identifiants
pubmed: 34873149
doi: 10.1038/s41398-021-01677-0
pii: 10.1038/s41398-021-01677-0
pmc: PMC8648734
doi:
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
618Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM140287
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG011138
Pays : United States
Organisme : NIA NIH HHS
ID : U24 AG021886
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG032984
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG061351
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG068026
Pays : United States
Organisme : NHGRI NIH HHS
ID : R35 HG010718
Pays : United States
Informations de copyright
© 2021. The Author(s).
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