title: Deep sequencing of the LRRK2 gene in 14,002 individuals reveals evidence of purifying selection and independent origin of the p.Arg1628Pro mutation in Europe.
abstract: Genetic variation in LRRK2 predisposes to Parkinson disease (PD), which underpins its development as a therapeutic target. Here, we aimed to identify novel genotype-phenotype associations that might support developing LRRK2 therapies for other conditions. We sequenced the 51 exons of LRRK2 in cases comprising 12 common diseases (n = 9,582), and in 4,420 population controls. We identified 739 single-nucleotide variants, 62% of which were observed in only one person, including 316 novel exonic variants. We found evidence of purifying selection for the LRRK2 gene and a trend suggesting that this is more pronounced in the central (ROC-COR-kinase) core protein domains of LRRK2 than the flanking domains. Population genetic analyses revealed that LRRK2 is not especially polymorphic or differentiated in comparison to 201 other drug target genes. Among Europeans, we identified 17 carriers (0.13%) of pathogenic LRRK2 mutations that were not significantly enriched within any disease or in those reporting a family history of PD. Analysis of pathogenic mutations within Europe reveals that the p.Arg1628Pro (c4883G>C) mutation arose independently in Europe and Asia. Taken together, these findings demonstrate how targeted deep sequencing can help to reveal fundamental characteristics of clinically important loci.
authors.affiliation: Quantitative Sciences, Research and Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, England, United Kingdom. justin.p.rubio@gsk.com
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
authors.forename: Simon
authors.initials: S
authors.lastname: Topp
authors.forename: Liling
authors.initials: L
authors.lastname: Warren
authors.forename: Pamela L
authors.initials: PL
authors.lastname: St Jean
authors.forename: Daniel
authors.initials: D
authors.lastname: Wegmann
authors.forename: Darren
authors.initials: D
authors.lastname: Kessner
authors.forename: John
authors.initials: J
authors.lastname: Novembre
authors.forename: Judong
authors.initials: J
authors.lastname: Shen
authors.forename: Dana
authors.initials: D
authors.lastname: Fraser
authors.forename: Jennifer
authors.initials: J
authors.lastname: Aponte
authors.forename: Keith
authors.initials: K
authors.lastname: Nangle
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Ehm
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Chissoe
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Mooser
mesh_terms: D005060:Europe; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases