03478nas a2200697   4500000000100000008004100001260000900042653002500051653001000076653001800086653001000104653003000114653003100144653003200175653001100207653001200218653005800230653000900288653002200297653003600319653003700355653002800392653001900420100001500439700001200454700001300466700001500479700001400494700001300508700001300521700001200534700001300546700001300559700001200572700001800584700006500602700001600667700001200683700001300695700001400708700001300722700002000735700001300755700001400768700001200782700001600794700001000810700001300820700001100833700001900844700001200863700001200875700001400887245009500901856007700996300001101073490000601084050001701090520165901107022001402766       2013                            d  c201310aAlternative splicing10aBrain10aCrohn Disease10aExons10aGene Expression Profiling10aGene Expression Regulation10aGenetic Association Studies10aHumans10aleprosy10aLeucine-Rich Repeat Serine-Threonine Protein Kinase-210aMale10aParkinson Disease10aPolymorphism, Single Nucleotide10aProtein-Serine-Threonine Kinases10aQuantitative Trait Loci10aRNA, Messenger1 aTrabzuni D1 aRyten M1 aEmmett W1 aRamasamy A1 aLackner K1 aZeller T1 aWalker R1 aSmith C1 aLewis PA1 aMamais A1 aSilva R1 aVandrovcova J1 aInternational Parkinson Disease Genomics Consortium (IPDGC) 1 aHernandez D1 aNalls M1 aSharma M1 aGarnier S1 aLesage S1 aSimon-Sanchez J1 aGasser T1 aHeutink P1 aBrice A1 aSingleton A1 aCai H1 aSchadt E1 aWood N1 aBandopadhyay R1 aWeale M1 aHardy J1 aPlagnol V00aFine-mapping, gene expression and splicing analysis of the disease associated LRRK2 locus.  uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742662/pdf/pone.0070724.pdf  ae707240 v8  aTRABZUNI20133 a<p>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. </p>  a1932-6203