Genomewide linkage study of modifiers of LRRK2-related Parkinson's disease

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.