Assessing the role of polygenic background on the penetrance of monogenic forms in Parkinson's disease.

BackgroundSeveral rare and common variants are associated with Parkinsons disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinsons disease. To address this issue, we investigated whether a PRS calculated from significant GWAS SNPs affects the penetrance of Parkinsons disease among carriers of rare monogenic variants in known Parkinsons disease genes and those with a family history. MethodsWe calculated the PRS based on common variants and selected the carriers of rare monogenic variants by using the exome data from UK Biobank. Individuals were divided into three risk categories based on PRS: low (<10%), intermediate (10%-90%), and high (>90%) risk groups. We then compared how PRS affects Parkinsons disease risk among carriers of rare monogenic variants and those with family-history. ResultsWe observed a two-fold higher odds ratio for a carrier of a monogenic variant that had a high PRS (OR 4.07,95% CI, 1.72-8.08) compared to carriers with a low PRS (OR 1.91, 95% CI, 0.31-6.05). In the same line, carriers with a first-degree family history and with >90% PRS have even a higher risk of developing PD (OR 23.53, 95%CI 5.39-71.54) compared to those with <90% PRS (OR 9.54, 95% CI 3.32-21.65). ConclusionsOur results show that PRS, carrier status, and family history contribute independently and additively to the Parkinsons disease risk.