What does heritability of Alzheimer's disease represent?
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2023
2023
Historique:
received:
11
10
2022
accepted:
24
01
2023
medline:
1
5
2023
pubmed:
28
4
2023
entrez:
28
4
2023
Statut:
epublish
Résumé
Both late-onset Alzheimer's disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. We compute heritability in five large independent cohorts (N = 7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. SNP-based heritability of late onset Alzheimer's disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD = 8%] on average when the APOE region is excluded and an additional 1% [SD = 3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. The heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes.
Identifiants
pubmed: 37115753
doi: 10.1371/journal.pone.0281440
pii: PONE-D-22-27299
pmc: PMC10146480
doi:
Substances chimiques
Apolipoproteins E
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0281440Informations de copyright
Copyright: © 2023 Baker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have read the journal’s policy and have the following competing interests: MH hold shares in Vertex Pharmaceuticals. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents or patents, products in development or marketed products associated with this research to declare.
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