Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease.

Abstract:

:Type-1 reactions (T1R) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the genewise enrichment of rare protein-altering variants in 7 genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Genewise enrichment of nonsynonymous variants was tested with both kernel-based (sequence kernel association test [SKAT]) and burden methods. Of the 7 genes tested 2 showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (PSKAT-O = 1.6 × 10-4). This genewise association was driven almost entirely by the gain-of-function variant R1628P (P = 0.004; odds ratio = 0.29). The second genewise association was found for the Parkin coding gene PRKN (formerly PARK2) where 7 rare variants were enriched in T1R-affected cases (PSKAT-O = 7.4 × 10-5). Mutations in both PRKN and LRRK2 are known causes of Parkinson's disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that amino acids in Parkin targeted by nonsynonymous T1R-risk mutations were also enriched for mutations implicated in PD (P = 1.5 × 10-4). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity.

authors

Fava VM,Xu YZ,Lettre G,Van Thuc N,Orlova M,Thai VH,Tao S,Croteau N,Eldeeb MA,MacDougall EJ,Cambri G,Lahiri R,Adams L,Fon EA,Trempe JF,Cobat A,Alcaïs A,Abel L,Schurr E

doi

10.1073/pnas.1901805116

subject

Has Abstract

pub_date

2019-07-30 00:00:00

pages

15616-15624

issue

31

eissn

0027-8424

issn

1091-6490

pii

1901805116

journal_volume

116

pub_type

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