Objective: To analyze the UKBiobank cohorts of Parkinson’s disease (PD) and Cutaneous Malignant Melanoma to uncover shared genetic factors explained by ultra-rare damaging coding variants (URVs).

Background: Epidemiological data show that, overall, PD patients have a low prevalence of cancers, but they have a 3.6-fold higher risk to develop melanoma. Recently, common genetic variants (minor allele frequency, MAF>0.01) were found to explain a 17% of the shared genetic heritability for both diseases, however the contribution of rare damaging coding variants (MAF<0.01) remains unknown.

Method: We used the UKBiobank whole-exome sequencing cohort including 450K individuals. After variant annotation and prioritization, we used the Burden Heritability Regression (BHR) pipeline to calculate heritability estimates in PD and melanoma independently, and a genetic correlation between both diseases using nonsynonymous damaging URVs (CADD score > 20. MAF<1e-3).

Results: After individual level quality controls, we obtained 2,669 PD cases, 377,111 controls, along with 3,278 Melanoma cases, and 376,502 controls. Variant prioritization resulted in 1,747,193 URVs across 20,005 unique genes. For the PD cohort, gene-wise burden analysis showed seven significant genes after multiple testing correction, and using a global PD prevalence of 0.3%, we observed that damaging URVs explained a 0.77% (SE=0.0048) of the PD genetic heritability in the liability scale. For the melanoma cohort, we observed nine significant genes, and using a melanoma prevalence of 0.4%, we obtained a URV-explained heritability of 1.87% (SE=0.0042). In the bivariate analysis of both PD and melanoma cohorts, we obtained 12 significant genes, and the heritability correlation for all URVs (r_g) was 13.46% (SE=0.16) for both diseases.

Conclusion: We estimated the genetic heritability for PD and melanoma in the UKBiobank explained by damaging coding nonsynonymous URVs and identified a positive genetic correlation between both diseases. Analysis of indels and loss of function variants, and how single genes are contributing to heritability in both PD and Melanoma will be done to select genes for replication analyses in independent PD, melanoma, and PD-melanoma case-control cohorts. These results will help guide functional validation efforts to elucidate shared disease mechanism(s).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exome-wide-contribution-of-ultra-rare-variants-to-the-genetic-architecture-of-parkinsons-disease-and-cutaneous-malignant-melanoma/