LRRK2 coding variants and the risk of Parkinson’s disease

摘要: Abstract Background The leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (e.g. p.G2019S) and common non-coding rs76904798) with lower effect sizes that are associated Parkinson’s disease risk. Objectives This study aimed to investigate in a large meta-analysis whether the LRRK2 GWAS signal represented by rs76904798 is independently risk from coding variation, complex linkage disequilibrium structures p.G2019S 5’ haplotype account for association of variants. Methods We performed using imputed genotypes 17,838 cases, 13,404 proxy-cases 173,639 healthy controls European ancestry. excluded carriers and/or clarify role variation mediating risk, relatively assess independence rs76904798. also investigated co-inheritance p.G2019S, p.N2081D. Results remained significantly after excluding p.R1514Q p.N2081D were frequently co-inherited allele distribution p.S1647T changed among cases removing carriers. Conclusions These data suggest previously linked (p.N551K, p.R1398H, p.M1646T p.N2081D) do not drive signal. data, however, preclude independent p.N551K-p.R1398H altered