Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus.
Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in...
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2013
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oai:doaj.org-article:aa919c6789b341e69f7b3a79a679c38a2021-11-18T08:59:57ZFine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus.1932-620310.1371/journal.pone.0070724https://doaj.org/article/aa919c6789b341e69f7b3a79a679c38a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23967090/?tool=EBIhttps://doaj.org/toc/1932-6203Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A>G, P = 2.56×10(-8), case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms.Daniah TrabzuniMina RytenWarren EmmettAdaikalavan RamasamyKarl J LacknerTanja ZellerRobert WalkerColin SmithPatrick A LewisAdamantios MamaisRohan de SilvaJana VandrovcovaInternational Parkinson Disease Genomics Consortium (IPDGC)Dena HernandezMichael A NallsManu SharmaSophie GarnierSuzanne LesageJavier Simon-SanchezThomas GasserPeter HeutinkAlexis BriceAndrew SingletonHuaibin CaiEric SchadtNicholas W WoodRina BandopadhyayMichael E WealeJohn HardyVincent PlagnolPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e70724 (2013) |
| institution |
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| collection |
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| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Daniah Trabzuni Mina Ryten Warren Emmett Adaikalavan Ramasamy Karl J Lackner Tanja Zeller Robert Walker Colin Smith Patrick A Lewis Adamantios Mamais Rohan de Silva Jana Vandrovcova International Parkinson Disease Genomics Consortium (IPDGC) Dena Hernandez Michael A Nalls Manu Sharma Sophie Garnier Suzanne Lesage Javier Simon-Sanchez Thomas Gasser Peter Heutink Alexis Brice Andrew Singleton Huaibin Cai Eric Schadt Nicholas W Wood Rina Bandopadhyay Michael E Weale John Hardy Vincent Plagnol Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. |
| description |
Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A>G, P = 2.56×10(-8), case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms. |
| format |
article |
| author |
Daniah Trabzuni Mina Ryten Warren Emmett Adaikalavan Ramasamy Karl J Lackner Tanja Zeller Robert Walker Colin Smith Patrick A Lewis Adamantios Mamais Rohan de Silva Jana Vandrovcova International Parkinson Disease Genomics Consortium (IPDGC) Dena Hernandez Michael A Nalls Manu Sharma Sophie Garnier Suzanne Lesage Javier Simon-Sanchez Thomas Gasser Peter Heutink Alexis Brice Andrew Singleton Huaibin Cai Eric Schadt Nicholas W Wood Rina Bandopadhyay Michael E Weale John Hardy Vincent Plagnol |
| author_facet |
Daniah Trabzuni Mina Ryten Warren Emmett Adaikalavan Ramasamy Karl J Lackner Tanja Zeller Robert Walker Colin Smith Patrick A Lewis Adamantios Mamais Rohan de Silva Jana Vandrovcova International Parkinson Disease Genomics Consortium (IPDGC) Dena Hernandez Michael A Nalls Manu Sharma Sophie Garnier Suzanne Lesage Javier Simon-Sanchez Thomas Gasser Peter Heutink Alexis Brice Andrew Singleton Huaibin Cai Eric Schadt Nicholas W Wood Rina Bandopadhyay Michael E Weale John Hardy Vincent Plagnol |
| author_sort |
Daniah Trabzuni |
| title |
Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. |
| title_short |
Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. |
| title_full |
Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. |
| title_fullStr |
Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. |
| title_full_unstemmed |
Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. |
| title_sort |
fine-mapping, gene expression and splicing analysis of the disease associated lrrk2 locus. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/aa919c6789b341e69f7b3a79a679c38a |
| work_keys_str_mv |
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