A transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease

Abstract Genome-wide association study (GWAS) has seen great strides in revealing initial insights into the genetic architecture of Parkinson’s disease (PD). Since GWAS signals often reside in non-coding regions, relatively few of the associations have implicated specific biological mechanisms. Here...

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Autores principales:	Shi Yao, Xi Zhang, Shu-Cheng Zou, Yong Zhu, Bo Li, Wei-Ping Kuang, Yan Guo, Xiao-Song Li, Liang Li, Xiao-Ye Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/095305286b2d417191ae25a4d675c824
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spelling	oai:doaj.org-article:095305286b2d417191ae25a4d675c8242021-12-02T17:41:18ZA transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease10.1038/s41531-021-00221-72373-8057https://doaj.org/article/095305286b2d417191ae25a4d675c8242021-09-01T00:00:00Zhttps://doi.org/10.1038/s41531-021-00221-7https://doaj.org/toc/2373-8057Abstract Genome-wide association study (GWAS) has seen great strides in revealing initial insights into the genetic architecture of Parkinson’s disease (PD). Since GWAS signals often reside in non-coding regions, relatively few of the associations have implicated specific biological mechanisms. Here, we aimed to integrate the GWAS results with large-scale expression quantitative trait loci (eQTL) in 13 brain tissues to identify candidate causal genes for PD. We conducted a transcriptome-wide association study (TWAS) for PD using the summary statistics of over 480,000 individuals from the most recent PD GWAS. We identified 18 genes significantly associated with PD after Bonferroni corrections. The most significant gene, LRRC37A2, was associated with PD in all 13 brain tissues, such as in the hypothalamus (P = 6.12 × 10−22) and nucleus accumbens basal ganglia (P = 5.62 × 10−21). We also identified eight conditionally independent genes, including four new genes at known PD loci: CD38, LRRC37A2, RNF40, and ZSWIM7. Through conditional analyses, we demonstrated that several of the GWAS significant signals on PD could be driven by genetically regulated gene expression. The most significant TWAS gene LRRC37A2 accounts for 0.855 of the GWAS signal at its loci, and ZSWIM7 accounts for all the GWAS signals at its loci. We further identified several phenotypes previously associated with PD by querying the single nucleotide polymorphisms (SNPs) in the final model of the identified genes in phenome databases. In conclusion, we prioritized genes that are likely to affect PD by using a TWAS approach and identified phenotypes associated with PD.Shi YaoXi ZhangShu-Cheng ZouYong ZhuBo LiWei-Ping KuangYan GuoXiao-Song LiLiang LiXiao-Ye WangNature PortfolioarticleNeurology. Diseases of the nervous systemRC346-429ENnpj Parkinson's Disease, Vol 7, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurology. Diseases of the nervous system RC346-429 Shi Yao Xi Zhang Shu-Cheng Zou Yong Zhu Bo Li Wei-Ping Kuang Yan Guo Xiao-Song Li Liang Li Xiao-Ye Wang A transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease
description	Abstract Genome-wide association study (GWAS) has seen great strides in revealing initial insights into the genetic architecture of Parkinson’s disease (PD). Since GWAS signals often reside in non-coding regions, relatively few of the associations have implicated specific biological mechanisms. Here, we aimed to integrate the GWAS results with large-scale expression quantitative trait loci (eQTL) in 13 brain tissues to identify candidate causal genes for PD. We conducted a transcriptome-wide association study (TWAS) for PD using the summary statistics of over 480,000 individuals from the most recent PD GWAS. We identified 18 genes significantly associated with PD after Bonferroni corrections. The most significant gene, LRRC37A2, was associated with PD in all 13 brain tissues, such as in the hypothalamus (P = 6.12 × 10−22) and nucleus accumbens basal ganglia (P = 5.62 × 10−21). We also identified eight conditionally independent genes, including four new genes at known PD loci: CD38, LRRC37A2, RNF40, and ZSWIM7. Through conditional analyses, we demonstrated that several of the GWAS significant signals on PD could be driven by genetically regulated gene expression. The most significant TWAS gene LRRC37A2 accounts for 0.855 of the GWAS signal at its loci, and ZSWIM7 accounts for all the GWAS signals at its loci. We further identified several phenotypes previously associated with PD by querying the single nucleotide polymorphisms (SNPs) in the final model of the identified genes in phenome databases. In conclusion, we prioritized genes that are likely to affect PD by using a TWAS approach and identified phenotypes associated with PD.
format	article
author	Shi Yao Xi Zhang Shu-Cheng Zou Yong Zhu Bo Li Wei-Ping Kuang Yan Guo Xiao-Song Li Liang Li Xiao-Ye Wang
author_facet	Shi Yao Xi Zhang Shu-Cheng Zou Yong Zhu Bo Li Wei-Ping Kuang Yan Guo Xiao-Song Li Liang Li Xiao-Ye Wang
author_sort	Shi Yao
title	A transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease
title_short	A transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease
title_full	A transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease
title_fullStr	A transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease
title_full_unstemmed	A transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease
title_sort	transcriptome-wide association study identifies susceptibility genes for parkinson’s disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/095305286b2d417191ae25a4d675c824
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A transcriptome-wide association study identifies susceptibility genes for Parkinson’s disease

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