Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition

Abstract The characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-w...

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Autores principales:	Nadav Brandes, Nathan Linial, Michal Linial
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a29e3e58309f454aa43a5fa62fc78f33
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spelling	oai:doaj.org-article:a29e3e58309f454aa43a5fa62fc78f332021-12-02T16:26:37ZGenetic association studies of alterations in protein function expose recessive effects on cancer predisposition10.1038/s41598-021-94252-y2045-2322https://doaj.org/article/a29e3e58309f454aa43a5fa62fc78f332021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94252-yhttps://doaj.org/toc/2045-2322Abstract The characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-wide association studies (GWAS). However, the results of such studies rarely provide biological insight or functional interpretation. In this study, we conducted a comprehensive analysis of cancer predisposition in the UK Biobank cohort using a new gene-based method for detecting protein-coding genes that are functionally interpretable. Specifically, we conducted proteome-wide association studies (PWAS) to identify genetic associations mediated by alterations to protein function. With PWAS, we identified 110 significant gene-cancer associations in 70 unique genomic regions across nine cancer types and pan-cancer. In 48 of the 110 PWAS associations (44%), estimated gene damage is associated with reduced rather than elevated cancer risk, suggesting a protective effect. Together with standard GWAS, we implicated 145 unique genomic loci with cancer risk. While most of these genomic regions are supported by external evidence, our results also highlight many novel loci. Based on the capacity of PWAS to detect non-additive genetic effects, we found that 46% of the PWAS-significant cancer regions exhibited exclusive recessive inheritance. These results highlight the importance of recessive genetic effects, without relying on familial studies. Finally, we show that many of the detected genes exert substantial cancer risk in the studied cohort determined by a quantitative functional description, suggesting their relevance for diagnosis and genetic consulting.Nadav BrandesNathan LinialMichal LinialNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nadav Brandes Nathan Linial Michal Linial Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition
description	Abstract The characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-wide association studies (GWAS). However, the results of such studies rarely provide biological insight or functional interpretation. In this study, we conducted a comprehensive analysis of cancer predisposition in the UK Biobank cohort using a new gene-based method for detecting protein-coding genes that are functionally interpretable. Specifically, we conducted proteome-wide association studies (PWAS) to identify genetic associations mediated by alterations to protein function. With PWAS, we identified 110 significant gene-cancer associations in 70 unique genomic regions across nine cancer types and pan-cancer. In 48 of the 110 PWAS associations (44%), estimated gene damage is associated with reduced rather than elevated cancer risk, suggesting a protective effect. Together with standard GWAS, we implicated 145 unique genomic loci with cancer risk. While most of these genomic regions are supported by external evidence, our results also highlight many novel loci. Based on the capacity of PWAS to detect non-additive genetic effects, we found that 46% of the PWAS-significant cancer regions exhibited exclusive recessive inheritance. These results highlight the importance of recessive genetic effects, without relying on familial studies. Finally, we show that many of the detected genes exert substantial cancer risk in the studied cohort determined by a quantitative functional description, suggesting their relevance for diagnosis and genetic consulting.
format	article
author	Nadav Brandes Nathan Linial Michal Linial
author_facet	Nadav Brandes Nathan Linial Michal Linial
author_sort	Nadav Brandes
title	Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition
title_short	Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition
title_full	Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition
title_fullStr	Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition
title_full_unstemmed	Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition
title_sort	genetic association studies of alterations in protein function expose recessive effects on cancer predisposition
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a29e3e58309f454aa43a5fa62fc78f33
work_keys_str_mv	AT nadavbrandes geneticassociationstudiesofalterationsinproteinfunctionexposerecessiveeffectsoncancerpredisposition AT nathanlinial geneticassociationstudiesofalterationsinproteinfunctionexposerecessiveeffectsoncancerpredisposition AT michallinial geneticassociationstudiesofalterationsinproteinfunctionexposerecessiveeffectsoncancerpredisposition
_version_	1718384008945991680

Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition

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