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.
Highlights
The role of Leucine-rich repeat kinase 2 (LRRK2) in human disease was first recognised in 2004 when dominant mutations in the LRRK2 gene were linked to Parkinson’s disease (PD)
To fine-map this locus and confirm that this result is independent of the previously described rare variant association at the nsSNP rs34637584/G2019S, we densely genotyped the LRRK2 region in the GWAS replication set of 5,802 PD cases and 5,556 controls using the ImmunoChip (2.3 typed SNPs per kb on average in the region defined by hg19 chr12:40,351,60140,830,814, see Methods and [21])
The strongest evidence of association in this conditional analysis was found for rs117762348 which is located 59 of LRRK2. rs117762348 is in moderate LD (D’ = 1, r2 = 0.31, Table S3) with the initial GWAS SNP rs1491942
Summary
The role of LRRK2 in human disease was first recognised in 2004 when dominant mutations in the LRRK2 gene were linked to Parkinson’s disease (PD). Rare genetic variants located in the LRRK2 gene contribute to a significant fraction of familial clustering of the disease [1]. Recent GWAS results suggest that common variants with a more modest effect on PD risk exist at this locus [4]. GWAS have implicated LRRK2 in the pathogenesis of Crohn’s disease (CD) and leprosy [5,6,7]. The mechanisms linking PD and the LRRK2 gene, and more generally the LRRK2 gene and human disease, remain largely unknown and are the focus of an intense research effort
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