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, Jahrgang 8, Nr. 8, 2013, S. e70724.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -