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See detailAssessing the role of polygenic background on the penetrance of monogenic forms in Parkinson\textquoterights disease. 2021.06.06.21253270
Hassanin, Emadeldin; May, Patrick UL; Aldisi, Rana et al

E-print/Working paper (2021)

Background: Several rare and common variants are associated with Parkinson's disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinson's disease ... [more ▼]

Background: Several rare and common variants are associated with Parkinson's disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinson's disease. To address this issue, we investigated whether a PRS calculated from significant GWAS SNPs affects the penetrance of Parkinson's disease among carriers of rare monogenic variants in known Parkinson's disease genes and those with a family history. Methods: We 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 Parkinson\textquoterights disease risk among carriers of rare monogenic variants and those with family-history. Results: We 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). Conclusions: Our results show that PRS, carrier status, and family history contribute independently and additively to the Parkinson's disease risk. [less ▲]

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See detailBreast and prostate cancer risk: the interplay of polygenic risk, high-impact monogenic variants, and family history 2021.06.04.21258277
Hassanin, Emadeldin; May, Patrick UL; Aldisi, Rana et al

E-print/Working paper (2021)

Purpose: Investigate to which extent polygenic risk scores (PRS), high-impact monogenic variants, and family history affect breast and prostate cancer risk by assessing cancer prevalence and cancer ... [more ▼]

Purpose: Investigate to which extent polygenic risk scores (PRS), high-impact monogenic variants, and family history affect breast and prostate cancer risk by assessing cancer prevalence and cancer cumulative lifetime incidence. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. carriers or non-carriers of high impact constitutive, monogenic variants in cancer susceptibility genes, 2. high or non-high PRS (90th percentile threshold), 3. with or without a family history of cancer. Multivariable logistic regression was used to compare the odds ratio (OR) across the different groups while Cox proportional hazards models were used to compute the cumulative incidence through life. Results Breast and prostate cancer cumulative incidence by age 70 is 7 and 5 for non-carriers with non-high PRS and reaches 37 and 32 among carriers of high-impact variants in cancer susceptibility genes with high PRS. The additional presence of family history is associated with a further increase of the risk of developing cancer reaching an OR of 14 and 21 for breast and prostate cancer, respectively. Conclusion: High PRS confers a cancer risk comparable to high-impact monogenic variants. Family history, monogenic variants, and PRS contribute additively to breast and prostate cancer risk. [less ▲]

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