Leonard, H. L. | Search bioRxiv

bioRxiv2019

Penetrance of Parkinson’s disease in LRRK2 p.G2019S carriers is modified by a polygenic risk score

BackgroundWhile the LRRK2 p.G2019S mutation has been demonstrated to be a strong risk factor for Parkinsons Disease (PD), factors that contribute to penetrance among carriers, other than aging, have not been well identified.\n\nObjectivesTo evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers.\n\nMethodsWe 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.\n\nResultsAfter 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).\n\nConclusionsOur 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.

genetics↗

bioRxiv2019

Genome-wide association study of Parkinson's disease progression biomarkers in 12 longitudinal patients' cohorts

BackgroundSeveral reports have identified different patterns of Parkinsons disease progression in individuals carrying missense variants in the GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinsons disease, however, has not been well studied. ObjectivesTo test the association between genetic variants and the clinical features and progression of Parkinsons disease on a genome-wide scale. MethodsWe accumulated individual data from 12 longitudinal cohorts in a total of 4,093 patients with 25,254 observations over a median of 3.81 years. Genome-wide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently-identified disease risk variants, were also investigated for the associations with these phenotypes. ResultsTwo variants were genome-wide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (HR 2.04 [1.58, 2.62], P-value = 3.46E-8). Rs61863020(G>A), an intergenic variant and eQTL for ADRA2A, was associated with a lower prevalence of insomnia at baseline (OR 0.63 [0,52, 0.75], P-value = 4.74E-8). In the targeted analysis, we found nine associations between known Parkinsons risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K, rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. ConclusionsWe identified novel genetic factors associated with heterogeneity of progression in Parkinsons disease. The results provide new insights into the pathogenesis of Parkinsons disease as well as patient stratification for clinical trials.

genetics↗