What does heritability of Alzheimer's disease represent?
<h4>Introduction</h4>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 he...
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0281440&type=printable |
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| author | Emily Baker Ganna Leonenko Karl Michael Schmidt Matthew Hill Amanda J Myers Maryam Shoai Itziar de Rojas Niccoló Tesi Henne Holstege Wiesje M van der Flier Yolande A L Pijnenburg Agustin Ruiz John Hardy Sven van der Lee Valentina Escott-Price |
| author_facet | Emily Baker Ganna Leonenko Karl Michael Schmidt Matthew Hill Amanda J Myers Maryam Shoai Itziar de Rojas Niccoló Tesi Henne Holstege Wiesje M van der Flier Yolande A L Pijnenburg Agustin Ruiz John Hardy Sven van der Lee Valentina Escott-Price |
| author_sort | Emily Baker |
| collection | DOAJ |
| description | <h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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. |
| format | Article |
| id | doaj-art-51b3981e072d44fe9ab7932f0edb784c |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-51b3981e072d44fe9ab7932f0edb784c2025-08-20T03:46:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01184e028144010.1371/journal.pone.0281440What does heritability of Alzheimer's disease represent?Emily BakerGanna LeonenkoKarl Michael SchmidtMatthew HillAmanda J MyersMaryam ShoaiItziar de RojasNiccoló TesiHenne HolstegeWiesje M van der FlierYolande A L PijnenburgAgustin RuizJohn HardySven van der LeeValentina Escott-Price<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0281440&type=printable |
| spellingShingle | Emily Baker Ganna Leonenko Karl Michael Schmidt Matthew Hill Amanda J Myers Maryam Shoai Itziar de Rojas Niccoló Tesi Henne Holstege Wiesje M van der Flier Yolande A L Pijnenburg Agustin Ruiz John Hardy Sven van der Lee Valentina Escott-Price What does heritability of Alzheimer's disease represent? PLoS ONE |
| title | What does heritability of Alzheimer's disease represent? |
| title_full | What does heritability of Alzheimer's disease represent? |
| title_fullStr | What does heritability of Alzheimer's disease represent? |
| title_full_unstemmed | What does heritability of Alzheimer's disease represent? |
| title_short | What does heritability of Alzheimer's disease represent? |
| title_sort | what does heritability of alzheimer s disease represent |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0281440&type=printable |
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