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Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus

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Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. / Trabzuni, Daniah; Ryten, Mina; Emmett, Warren; Ramasamy, Adaikalavan; Lackner, Karl J; Zeller, Tanja; Walker, Robert; Smith, Colin; Lewis, Patrick A; Mamais, Adamantios; de Silva, Rohan; Vandrovcova, Jana; Hernandez, Dena; Nalls, Michael A; Sharma, Manu; Garnier, Sophie; Lesage, Suzanne; Simon-Sanchez, Javier; Gasser, Thomas; Heutink, Peter; Brice, Alexis; Singleton, Andrew; Cai, Huaibin; Schadt, Eric; Wood, Nicholas W; Bandopadhyay, Rina; Weale, Michael E; Hardy, John; Plagnol, Vincent; International Parkinson Disease Genomics Consortium (IPDGC).

In: PLOS ONE, Vol. 8, No. 8, 2013, p. e70724.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Trabzuni, D, Ryten, M, Emmett, W, Ramasamy, A, Lackner, KJ, Zeller, T, Walker, R, Smith, C, Lewis, PA, Mamais, A, de Silva, R, Vandrovcova, J, Hernandez, D, Nalls, MA, Sharma, M, Garnier, S, Lesage, S, Simon-Sanchez, J, Gasser, T, Heutink, P, Brice, A, Singleton, A, Cai, H, Schadt, E, Wood, NW, Bandopadhyay, R, Weale, ME, Hardy, J, Plagnol, V & International Parkinson Disease Genomics Consortium (IPDGC) 2013, 'Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus', PLOS ONE, vol. 8, no. 8, pp. e70724. https://doi.org/10.1371/journal.pone.0070724

APA

Trabzuni, D., Ryten, M., Emmett, W., Ramasamy, A., Lackner, K. J., Zeller, T., Walker, R., Smith, C., Lewis, P. A., Mamais, A., de Silva, R., Vandrovcova, J., Hernandez, D., Nalls, M. A., Sharma, M., Garnier, S., Lesage, S., Simon-Sanchez, J., Gasser, T., ... International Parkinson Disease Genomics Consortium (IPDGC) (2013). Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. PLOS ONE, 8(8), e70724. https://doi.org/10.1371/journal.pone.0070724

Vancouver

Trabzuni D, Ryten M, Emmett W, Ramasamy A, Lackner KJ, Zeller T et al. Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus. PLOS ONE. 2013;8(8):e70724. https://doi.org/10.1371/journal.pone.0070724

Bibtex

@article{8ada2b534f3e429da0548c0fd963d3da,
title = "Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus",
abstract = "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. ",
keywords = "Alternative Splicing, Brain/metabolism, Crohn Disease/genetics, Exons, Gene Expression Profiling, Gene Expression Regulation, Genetic Association Studies, Humans, Leprosy, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Parkinson Disease/genetics, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases/genetics, Quantitative Trait Loci, RNA, Messenger/genetics",
author = "Daniah Trabzuni and Mina Ryten and Warren Emmett and Adaikalavan Ramasamy and Lackner, {Karl J} and Tanja Zeller and Robert Walker and Colin Smith and Lewis, {Patrick A} and Adamantios Mamais and {de Silva}, Rohan and Jana Vandrovcova and Dena Hernandez and Nalls, {Michael A} and Manu Sharma and Sophie Garnier and Suzanne Lesage and Javier Simon-Sanchez and Thomas Gasser and Peter Heutink and Alexis Brice and Andrew Singleton and Huaibin Cai and Eric Schadt and Wood, {Nicholas W} and Rina Bandopadhyay and Weale, {Michael E} and John Hardy and Vincent Plagnol and {International Parkinson Disease Genomics Consortium (IPDGC)}",
year = "2013",
doi = "10.1371/journal.pone.0070724",
language = "English",
volume = "8",
pages = "e70724",
journal = "PLOS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

RIS

TY - JOUR

T1 - Fine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus

AU - Trabzuni, Daniah

AU - Ryten, Mina

AU - Emmett, Warren

AU - Ramasamy, Adaikalavan

AU - Lackner, Karl J

AU - Zeller, Tanja

AU - Walker, Robert

AU - Smith, Colin

AU - Lewis, Patrick A

AU - Mamais, Adamantios

AU - de Silva, Rohan

AU - Vandrovcova, Jana

AU - Hernandez, Dena

AU - Nalls, Michael A

AU - Sharma, Manu

AU - Garnier, Sophie

AU - Lesage, Suzanne

AU - Simon-Sanchez, Javier

AU - Gasser, Thomas

AU - Heutink, Peter

AU - Brice, Alexis

AU - Singleton, Andrew

AU - Cai, Huaibin

AU - Schadt, Eric

AU - Wood, Nicholas W

AU - Bandopadhyay, Rina

AU - Weale, Michael E

AU - Hardy, John

AU - Plagnol, Vincent

AU - International Parkinson Disease Genomics Consortium (IPDGC)

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Alternative Splicing

KW - Brain/metabolism

KW - Crohn Disease/genetics

KW - Exons

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Genetic Association Studies

KW - Humans

KW - Leprosy

KW - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

KW - Male

KW - Parkinson Disease/genetics

KW - Polymorphism, Single Nucleotide

KW - Protein-Serine-Threonine Kinases/genetics

KW - Quantitative Trait Loci

KW - RNA, Messenger/genetics

U2 - 10.1371/journal.pone.0070724

DO - 10.1371/journal.pone.0070724

M3 - SCORING: Journal article

C2 - 23967090

VL - 8

SP - e70724

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 8

ER -