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.
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors: Daniah
authors: D
authors: Trabzuni
authors: Mina
authors: M
authors: Ryten
authors: Warren
authors: W
authors: Emmett
authors: Adaikalavan
authors: A
authors: Ramasamy
authors: Karl J
authors: KJ
authors: Lackner
authors: Tanja
authors: T
authors: Zeller
authors: Robert
authors: R
authors: Walker
authors: Colin
authors: C
authors: Smith
authors: Patrick A
authors: PA
authors: Lewis
authors: Adamantios
authors: A
authors: Mamais
authors: Rohan
authors: R
authors: de Silva
authors: Jana
authors: J
authors: Vandrovcova
authors: Dena
authors: D
authors: Hernandez
authors: Michael A
authors: MA
authors: Nalls
authors: Manu
authors: M
authors: Sharma
authors: Sophie
authors: S
authors: Garnier
authors: Suzanne
authors: S
authors: Lesage
authors: Javier
authors: J
authors: Simon-Sanchez
authors: Thomas
authors: T
authors: Gasser
authors: Peter
authors: P
authors: Heutink
authors: Alexis
authors: A
authors: Brice
authors: Andrew
authors: A
authors: Singleton
authors: Huaibin
authors: H
authors: Cai
authors: Eric
authors: E
authors: Schadt
authors: Nicholas W
authors: NW
authors: Wood
authors: Rina
authors: R
authors: Bandopadhyay
authors: Michael E
authors: ME
authors: Weale
authors: John
authors: J
authors: Hardy
authors: Vincent
authors: V
authors: Plagnol
mesh_terms: D017398:Alternative Splicing; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics; D005091:Exons; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D007918:Leprosy; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D010300:Parkinson Disease / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
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