Fine-scale patterns of population stratification confound rare variant association tests.

Advances in next-generation sequencing technology have enabled systematic exploration of the contribution of rare variation to Mendelian and complex diseases. Although it is well known that population stratification can generate spurious associations with common alleles, its impact on rare variant a...

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Autores principales:	Timothy D O'Connor, Adam Kiezun, Michael Bamshad, Stephen S Rich, Joshua D Smith, Emily Turner, NHLBIGO Exome Sequencing Project, ESP Population Genetics, Statistical Analysis Working Group, Suzanne M Leal, Joshua M Akey
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/73c9803e1e2e43ad8c0ff68ad219753a
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spelling	oai:doaj.org-article:73c9803e1e2e43ad8c0ff68ad219753a2021-11-18T07:38:38ZFine-scale patterns of population stratification confound rare variant association tests.1932-620310.1371/journal.pone.0065834https://doaj.org/article/73c9803e1e2e43ad8c0ff68ad219753a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23861739/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Advances in next-generation sequencing technology have enabled systematic exploration of the contribution of rare variation to Mendelian and complex diseases. Although it is well known that population stratification can generate spurious associations with common alleles, its impact on rare variant association methods remains poorly understood. Here, we performed exhaustive coalescent simulations with demographic parameters calibrated from exome sequence data to evaluate the performance of nine rare variant association methods in the presence of fine-scale population structure. We find that all methods have an inflated spurious association rate for parameter values that are consistent with levels of differentiation typical of European populations. For example, at a nominal significance level of 5%, some test statistics have a spurious association rate as high as 40%. Finally, we empirically assess the impact of population stratification in a large data set of 4,298 European American exomes. Our results have important implications for the design, analysis, and interpretation of rare variant genome-wide association studies.Timothy D O'ConnorAdam KiezunMichael BamshadStephen S RichJoshua D SmithEmily TurnerNHLBIGO Exome Sequencing ProjectESP Population Genetics, Statistical Analysis Working GroupSuzanne M LealJoshua M AkeyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e65834 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Timothy D O'Connor Adam Kiezun Michael Bamshad Stephen S Rich Joshua D Smith Emily Turner NHLBIGO Exome Sequencing Project ESP Population Genetics, Statistical Analysis Working Group Suzanne M Leal Joshua M Akey Fine-scale patterns of population stratification confound rare variant association tests.
description	Advances in next-generation sequencing technology have enabled systematic exploration of the contribution of rare variation to Mendelian and complex diseases. Although it is well known that population stratification can generate spurious associations with common alleles, its impact on rare variant association methods remains poorly understood. Here, we performed exhaustive coalescent simulations with demographic parameters calibrated from exome sequence data to evaluate the performance of nine rare variant association methods in the presence of fine-scale population structure. We find that all methods have an inflated spurious association rate for parameter values that are consistent with levels of differentiation typical of European populations. For example, at a nominal significance level of 5%, some test statistics have a spurious association rate as high as 40%. Finally, we empirically assess the impact of population stratification in a large data set of 4,298 European American exomes. Our results have important implications for the design, analysis, and interpretation of rare variant genome-wide association studies.
format	article
author	Timothy D O'Connor Adam Kiezun Michael Bamshad Stephen S Rich Joshua D Smith Emily Turner NHLBIGO Exome Sequencing Project ESP Population Genetics, Statistical Analysis Working Group Suzanne M Leal Joshua M Akey
author_facet	Timothy D O'Connor Adam Kiezun Michael Bamshad Stephen S Rich Joshua D Smith Emily Turner NHLBIGO Exome Sequencing Project ESP Population Genetics, Statistical Analysis Working Group Suzanne M Leal Joshua M Akey
author_sort	Timothy D O'Connor
title	Fine-scale patterns of population stratification confound rare variant association tests.
title_short	Fine-scale patterns of population stratification confound rare variant association tests.
title_full	Fine-scale patterns of population stratification confound rare variant association tests.
title_fullStr	Fine-scale patterns of population stratification confound rare variant association tests.
title_full_unstemmed	Fine-scale patterns of population stratification confound rare variant association tests.
title_sort	fine-scale patterns of population stratification confound rare variant association tests.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/73c9803e1e2e43ad8c0ff68ad219753a
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Fine-scale patterns of population stratification confound rare variant association tests.

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