title: Genomewide linkage study of modifiers of LRRK2-related Parkinson's disease.
abstract: Mutations in the leucine-rich repeat kinase 2 gene, located at 12q12, are the most common known genetic causes of Parkinson's disease. Studies of leucine-rich repeat kinase 2 mutation carriers have shown incomplete and age-dependent penetrance, and previous studies have suggested that inherited susceptibility factors may modify the penetrance of leucine-rich repeat kinase 2 mutations. Genomewide linkage to age of onset of leucine-rich repeat kinase 2-related Parkinson's disease was evaluated in a sample of 113 leucine-rich repeat kinase 2 mutation carriers from 64 families using single-nucleotide polymorphism data from the Illumina HumanCNV370 genotyping array. Association between onset age and single-nucleotide polymorphisms under suggestive linkage peaks was also evaluated. The top logarithmic odds score for onset age (logarithmic odds score = 2.43) was in the chromosome 1q32.1 region. Moderate linkage to onset was also identified at 16q12.1 (logarithmic odds score = 1.58). Examination of single-nucleotide polymorphism association to Parkinson's disease onset under the linkage peaks revealed no statistically significant single-nucleotide polymorphism associations. The 2 novel genomic regions identified may harbor modifiers of leucine-rich repeat kinase 2-related Parkinson's disease onset age or penetrance, and further study of these regions may provide important insight into leucine-rich repeat kinase 2-related Parkinson's disease.
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, USA. jlatoure@bu.edu
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
authors.forename: Audrey E
authors.initials: AE
authors.lastname: Hendricks
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.forename: Cheryl
authors.initials: C
authors.lastname: Halter
authors.forename: William C
authors.initials: WC
authors.lastname: Nichols
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Anita L
authors.initials: AL
authors.lastname: Destefano
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025341:Principal Component Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases