Rare variants regulate expression of nearby individual genes in multiple tissues.

The rapid decrease in sequencing cost has enabled genetic studies to discover rare variants associated with complex diseases and traits. Once this association is identified, the next step is to understand the genetic mechanism of rare variants on how the variants influence diseases. Similar to the h...

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Autores principales:	Jiajin Li, Nahyun Kong, Buhm Han, Jae Hoon Sul
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/1ecd002ea1c34e409a4edb230dba15e1
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spelling	oai:doaj.org-article:1ecd002ea1c34e409a4edb230dba15e12021-12-02T20:02:43ZRare variants regulate expression of nearby individual genes in multiple tissues.1553-73901553-740410.1371/journal.pgen.1009596https://doaj.org/article/1ecd002ea1c34e409a4edb230dba15e12021-06-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009596https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The rapid decrease in sequencing cost has enabled genetic studies to discover rare variants associated with complex diseases and traits. Once this association is identified, the next step is to understand the genetic mechanism of rare variants on how the variants influence diseases. Similar to the hypothesis of common variants, rare variants may affect diseases by regulating gene expression, and recently, several studies have identified the effects of rare variants on gene expression using heritability and expression outlier analyses. However, identifying individual genes whose expression is regulated by rare variants has been challenging due to the relatively small sample size of expression quantitative trait loci studies and statistical approaches not optimized to detect the effects of rare variants. In this study, we analyze whole-genome sequencing and RNA-seq data of 681 European individuals collected for the Genotype-Tissue Expression (GTEx) project (v8) to identify individual genes in 49 human tissues whose expression is regulated by rare variants. To improve statistical power, we develop an approach based on a likelihood ratio test that combines effects of multiple rare variants in a nonlinear manner and has higher power than previous approaches. Using GTEx data, we identify many genes regulated by rare variants, and some of them are only regulated by rare variants and not by common variants. We also find that genes regulated by rare variants are enriched for expression outliers and disease-causing genes. These results suggest the regulatory effects of rare variants, which would be important in interpreting associations of rare variants with complex traits.Jiajin LiNahyun KongBuhm HanJae Hoon SulPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 6, p e1009596 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Jiajin Li Nahyun Kong Buhm Han Jae Hoon Sul Rare variants regulate expression of nearby individual genes in multiple tissues.
description	The rapid decrease in sequencing cost has enabled genetic studies to discover rare variants associated with complex diseases and traits. Once this association is identified, the next step is to understand the genetic mechanism of rare variants on how the variants influence diseases. Similar to the hypothesis of common variants, rare variants may affect diseases by regulating gene expression, and recently, several studies have identified the effects of rare variants on gene expression using heritability and expression outlier analyses. However, identifying individual genes whose expression is regulated by rare variants has been challenging due to the relatively small sample size of expression quantitative trait loci studies and statistical approaches not optimized to detect the effects of rare variants. In this study, we analyze whole-genome sequencing and RNA-seq data of 681 European individuals collected for the Genotype-Tissue Expression (GTEx) project (v8) to identify individual genes in 49 human tissues whose expression is regulated by rare variants. To improve statistical power, we develop an approach based on a likelihood ratio test that combines effects of multiple rare variants in a nonlinear manner and has higher power than previous approaches. Using GTEx data, we identify many genes regulated by rare variants, and some of them are only regulated by rare variants and not by common variants. We also find that genes regulated by rare variants are enriched for expression outliers and disease-causing genes. These results suggest the regulatory effects of rare variants, which would be important in interpreting associations of rare variants with complex traits.
format	article
author	Jiajin Li Nahyun Kong Buhm Han Jae Hoon Sul
author_facet	Jiajin Li Nahyun Kong Buhm Han Jae Hoon Sul
author_sort	Jiajin Li
title	Rare variants regulate expression of nearby individual genes in multiple tissues.
title_short	Rare variants regulate expression of nearby individual genes in multiple tissues.
title_full	Rare variants regulate expression of nearby individual genes in multiple tissues.
title_fullStr	Rare variants regulate expression of nearby individual genes in multiple tissues.
title_full_unstemmed	Rare variants regulate expression of nearby individual genes in multiple tissues.
title_sort	rare variants regulate expression of nearby individual genes in multiple tissues.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/1ecd002ea1c34e409a4edb230dba15e1
work_keys_str_mv	AT jiajinli rarevariantsregulateexpressionofnearbyindividualgenesinmultipletissues AT nahyunkong rarevariantsregulateexpressionofnearbyindividualgenesinmultipletissues AT buhmhan rarevariantsregulateexpressionofnearbyindividualgenesinmultipletissues AT jaehoonsul rarevariantsregulateexpressionofnearbyindividualgenesinmultipletissues
_version_	1718375646539808768

Rare variants regulate expression of nearby individual genes in multiple tissues.

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