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Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.


ABSTRACT: The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.

SUBMITTER: Brown EE 

PROVIDER: S-EPMC7762821 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

Brown Emmeline E EE   Blauwendraat Cornelis C   Trinh Joanne J   Rizig Mie M   Nalls Mike A MA   Leveille Etienne E   Ruskey Jennifer A JA   Jonvik Hallgeir H   Tan Manuela M X MMX   Bandres-Ciga Sara S   Hassin-Baer Sharon S   Brockmann Kathrin K   Infante Jon J   Tolosa Eduardo E   Ezquerra Mario M   Ben Romdhan Sawssan S   Benmahdjoub Mustapha M   Arezki Mohamed M   Mhiri Chokri C   Hardy John J   Singleton Andrew B AB   Alcalay Roy N RN   Gasser Thomas T   Grosset Donald G DG   Williams Nigel M NM   Pittman Alan A   Gan-Or Ziv Z   Fernandez-Santiago Ruben R   Brice Alexis A   Lesage Suzanne S   Farrer Matthew M   Wood Nicholas N   Morris Huw R HR  

Neurobiology of aging 20200713


The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene ma  ...[more]

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