Key Points Question What genes and genomic processes underlie risk of sporadic Parkinson disease? Findings This genetic association study integrated Parkinson disease genome-wide association study data and brain-derived gene regulation data using various complementary bioinformatic tools and identified 11 candidate genes with evidence of disease-associated regulatory changes. Coexpression and protein level analyses of these genes demonstrated a significant functional association with known mendelian Parkinson disease genes. Meaning This study suggests that gene regulation data may be used to identify candidate genes and pathways involved in sporadic Parkinson disease.

A BS TRACT: Background: Although the leucine-rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for 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 data sets: one from a case-control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta-analyzed. We also explored the interaction of age and PRS.Results: After excluding eight homozygotes, 833 p. G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation 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 etiological consequences and potential impact on the selection of subjects for clinical trials.

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We did not find any evidence supporting the association of NALCN with cervical dystonia, indicating that this gene is not implicated in the pathogenesis of this disorder in our cervical dystonia population.