RT Journal Article
SR Electronic
T1 Analysis of <em>DNM3</em> and <em>VAMP4</em> as genetic modifiers of <em>LRRK2</em> Parkinson’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 686550
DO 10.1101/686550
A1 EE Brown
A1 C Blauwendraat
A1 J Trinh
A1 M Rizig
A1 MA Nalls
A1 E Leveille
A1 JA Ruskey
A1 H Jonvik
A1 MMX Tan
A1 S Bandres-Ciga
A1 S Hassin-Baer
A1 K Brockmann
A1 J Infante
A1 E Tolosa
A1 M Ezquerra
A1 S Benromdhan
A1 M Benmahdjoub
A1 J Hardy
A1 AB Singleton
A1 RN Alcalay
A1 T Gasser
A1 D Grosset
A1 NM Williams
A1 A Pittman
A1 Z Gan-Or
A1 R Fernandez-Santiago
A1 A Brice
A1 S Lesage
A1 M Farrer
A1 N Wood
A1 HR Morris
A1 on behalf of the International Parkinson Disease Genomics Consortium (IPDGC)
YR 2019
UL http://biorxiv.org/content/early/2019/07/29/686550.abstract
AB Objective To assess genetic modifiers of Parkinson’s disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk allelesMethods We analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).Results There was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = −1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = −2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037).Interpretation Analysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4.