TY - JOUR T1 - Penetrance of Parkinson’s disease in <em>LRRK2</em> p.G2019S carriers is modified by a polygenic risk score JF - bioRxiv DO - 10.1101/738260 SP - 738260 AU - Hirotaka Iwaki AU - Cornelis Blauwendraat AU - Mary B. Makarious AU - Sara Bandrés-Ciga AU - Hampton L. Leonard AU - J. Raphael Gibbs AU - Dena G. Hernandez AU - Sonia W. Scholz AU - Faraz Faghri AU - International Parkinson’s Disease Genomics Consortium (IPDGC) AU - Mike A. Nalls AU - Andrew B. Singleton Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/08/16/738260.1.abstract N2 - Background While the LRRK2 p.G2019S mutation has been demonstrated to be a strong risk factor for Parkinson’s Disease (PD), factors that contribute to penetrance among carriers, other than aging, have not been well identified.Objectives To evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers.Methods We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two datasets: one from a case-control setting without selection of mutation carriers, and the other from a population sampling. The associations between PRS constructed from 89 variants reported in Nalls et al. and PD were tested and meta-analyzed. We also explored the interaction of age and PRS.Results After excluding 8 homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. PRS was associated with a higher penetrance of PD (OR 1.34, 95% C.I. [1.09, 1.64] per +1 SD, P = 0.005). In addition, associations with PRS and penetrance were stronger in the younger participants (main effect: OR 1.28 [1.04, 1.58] per +1 SD, P = 0.022; interaction effect: OR 0.78 [0.64, 0.94] per +1 SD and +10 years of age, P = 0.008).Conclusions Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiologic consequences and potential impact on the selection of subjects for clinical trials. ER -