The impact of age on genetic risk for common diseases.

Inherited genetic variation contributes to individual risk for many complex diseases and is increasingly being used for predictive patient stratification. Previous work has shown that genetic factors are not equally relevant to human traits across age and other contexts, though the reasons for such...

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Autores principales:	Xilin Jiang, Chris Holmes, Gil McVean
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/43f89e3741c548fcb9d7da36209ddb38
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spelling	oai:doaj.org-article:43f89e3741c548fcb9d7da36209ddb382021-12-02T20:02:51ZThe impact of age on genetic risk for common diseases.1553-73901553-740410.1371/journal.pgen.1009723https://doaj.org/article/43f89e3741c548fcb9d7da36209ddb382021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009723https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Inherited genetic variation contributes to individual risk for many complex diseases and is increasingly being used for predictive patient stratification. Previous work has shown that genetic factors are not equally relevant to human traits across age and other contexts, though the reasons for such variation are not clear. Here, we introduce methods to infer the form of the longitudinal relationship between genetic relative risk for disease and age and to test whether all genetic risk factors behave similarly. We use a proportional hazards model within an interval-based censoring methodology to estimate age-varying individual variant contributions to genetic relative risk for 24 common diseases within the British ancestry subset of UK Biobank, applying a Bayesian clustering approach to group variants by their relative risk profile over age and permutation tests for age dependency and multiplicity of profiles. We find evidence for age-varying relative risk profiles in nine diseases, including hypertension, skin cancer, atherosclerotic heart disease, hypothyroidism and calculus of gallbladder, several of which show evidence, albeit weak, for multiple distinct profiles of genetic relative risk. The predominant pattern shows genetic risk factors having the greatest relative impact on risk of early disease, with a monotonic decrease over time, at least for the majority of variants, although the magnitude and form of the decrease varies among diseases. As a consequence, for diseases where genetic relative risk decreases over age, genetic risk factors have stronger explanatory power among younger populations, compared to older ones. We show that these patterns cannot be explained by a simple model involving the presence of unobserved covariates such as environmental factors. We discuss possible models that can explain our observations and the implications for genetic risk prediction.Xilin JiangChris HolmesGil McVeanPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 8, p e1009723 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Xilin Jiang Chris Holmes Gil McVean The impact of age on genetic risk for common diseases.
description	Inherited genetic variation contributes to individual risk for many complex diseases and is increasingly being used for predictive patient stratification. Previous work has shown that genetic factors are not equally relevant to human traits across age and other contexts, though the reasons for such variation are not clear. Here, we introduce methods to infer the form of the longitudinal relationship between genetic relative risk for disease and age and to test whether all genetic risk factors behave similarly. We use a proportional hazards model within an interval-based censoring methodology to estimate age-varying individual variant contributions to genetic relative risk for 24 common diseases within the British ancestry subset of UK Biobank, applying a Bayesian clustering approach to group variants by their relative risk profile over age and permutation tests for age dependency and multiplicity of profiles. We find evidence for age-varying relative risk profiles in nine diseases, including hypertension, skin cancer, atherosclerotic heart disease, hypothyroidism and calculus of gallbladder, several of which show evidence, albeit weak, for multiple distinct profiles of genetic relative risk. The predominant pattern shows genetic risk factors having the greatest relative impact on risk of early disease, with a monotonic decrease over time, at least for the majority of variants, although the magnitude and form of the decrease varies among diseases. As a consequence, for diseases where genetic relative risk decreases over age, genetic risk factors have stronger explanatory power among younger populations, compared to older ones. We show that these patterns cannot be explained by a simple model involving the presence of unobserved covariates such as environmental factors. We discuss possible models that can explain our observations and the implications for genetic risk prediction.
format	article
author	Xilin Jiang Chris Holmes Gil McVean
author_facet	Xilin Jiang Chris Holmes Gil McVean
author_sort	Xilin Jiang
title	The impact of age on genetic risk for common diseases.
title_short	The impact of age on genetic risk for common diseases.
title_full	The impact of age on genetic risk for common diseases.
title_fullStr	The impact of age on genetic risk for common diseases.
title_full_unstemmed	The impact of age on genetic risk for common diseases.
title_sort	impact of age on genetic risk for common diseases.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/43f89e3741c548fcb9d7da36209ddb38
work_keys_str_mv	AT xilinjiang theimpactofageongeneticriskforcommondiseases AT chrisholmes theimpactofageongeneticriskforcommondiseases AT gilmcvean theimpactofageongeneticriskforcommondiseases AT xilinjiang impactofageongeneticriskforcommondiseases AT chrisholmes impactofageongeneticriskforcommondiseases AT gilmcvean impactofageongeneticriskforcommondiseases
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The impact of age on genetic risk for common diseases.

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