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What does heritability of Alzheimer’s disease represent?

Simmonds, Emily, Leonenko, Ganna ORCID:, Schmidt, Karl Michael ORCID:, Hill, Matthew, Myers, Amanda, Shoai, Maryam, de Rojas, Itziar, Tesi, Niccolo, Holstege, Henne, van der Flier, Wiesje, Pijnenburg, Yolande, Ruiz, Agustin, Hardy, John, van der Lee, Sven and Escott-Price, Valentina ORCID: 2023. What does heritability of Alzheimer’s disease represent? PLoS ONE 18 (4) , e0281440. 10.1371/journal.pone.0281440

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Introduction 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. Methods 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. Results 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. Conclusion 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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Public Library of Science
ISSN: 1932-6203
Funders: MRC
Date of First Compliant Deposit: 1 February 2023
Date of Acceptance: 24 January 2023
Last Modified: 10 Jun 2024 08:40

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