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Age-related late-onset disease heritability patterns and implications for genome-wide association studies

Genome-wide association studies (GWASs) and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritabi...

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Autor principal: Oliynyk, Roman Teo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573810/
https://www.ncbi.nlm.nih.gov/pubmed/31231601
http://dx.doi.org/10.7717/peerj.7168
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author Oliynyk, Roman Teo
author_facet Oliynyk, Roman Teo
author_sort Oliynyk, Roman Teo
collection PubMed
description Genome-wide association studies (GWASs) and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem. Computer simulations of polygenic late-onset diseases (LODs) in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores (PRSs) becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes. The incidence rate for LODs grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for GWASs overrepresent older individuals with lower PRSs, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and GWASs. It also explains the relatively constant-with-age heritability found for LODs of lower prevalence, exemplified by cancers.
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spelling pubmed-65738102019-06-21 Age-related late-onset disease heritability patterns and implications for genome-wide association studies Oliynyk, Roman Teo PeerJ Bioinformatics Genome-wide association studies (GWASs) and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem. Computer simulations of polygenic late-onset diseases (LODs) in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores (PRSs) becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes. The incidence rate for LODs grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for GWASs overrepresent older individuals with lower PRSs, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and GWASs. It also explains the relatively constant-with-age heritability found for LODs of lower prevalence, exemplified by cancers. PeerJ Inc. 2019-06-14 /pmc/articles/PMC6573810/ /pubmed/31231601 http://dx.doi.org/10.7717/peerj.7168 Text en © 2019 Oliynyk http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Bioinformatics
Oliynyk, Roman Teo
Age-related late-onset disease heritability patterns and implications for genome-wide association studies
title Age-related late-onset disease heritability patterns and implications for genome-wide association studies
title_full Age-related late-onset disease heritability patterns and implications for genome-wide association studies
title_fullStr Age-related late-onset disease heritability patterns and implications for genome-wide association studies
title_full_unstemmed Age-related late-onset disease heritability patterns and implications for genome-wide association studies
title_short Age-related late-onset disease heritability patterns and implications for genome-wide association studies
title_sort age-related late-onset disease heritability patterns and implications for genome-wide association studies
topic Bioinformatics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573810/
https://www.ncbi.nlm.nih.gov/pubmed/31231601
http://dx.doi.org/10.7717/peerj.7168
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