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LRRK2 coding variants and the risk of Parkinson's disease

By Julie Lake, Xylena Reed, Rebekah G. Langston, Mike A Nalls, Ziv Gan-Or, Mark R Cookson, Andrew B. Singleton, Cornelis Blauwendraat, Hampton Leonard, International Parkinson Disease Genomics Consortium (IPDGC)

Posted 23 Apr 2021
medRxiv DOI: 10.1101/2021.04.22.21255928

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

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