RESUMO
Introduction Polygenic Score (PGS) is a valuable method for assessing the estimated genetic liability to a given outcome or genetic variability contributing to a quantitative trait. While PRSs are widely used for complex traits, their application in uncovering shared genetic predisposition between phenotypes, i.e. when genetic variants influence more than one phenotype, remains limited. Methods We developed an R package, comorbidPGS, which facilitates a systematic evaluation of shared genetic effects among (cor)related phenotypes using PGSs. The comorbidPGS package takes as input a set of Single Nucleotide Polymorphisms (SNPs) along with their established effects on the original phenotype (Po), referred to as Po-PGS. It generates a comprehensive summary of effect(s) of Po-PGS on target phenotype(s) (Pt) with customisable graphical features. Results We applied comorbidPGS to investigate the shared genetic predisposition between phenotypes defining elevated blood pressure (Systolic Blood Pressure, SBP; Diastolic Blood Pressure, DBP; Pulse Pressure, PP) and several cancers (Breast Cancer, BrC; Pancreatic Cancer, PanC; Kidney Cancer, KidC; Prostate Cancer, PrC; Colorectal Cancer, CrC) using the European ancestry UK Biobank individuals and GWAS meta-analyses summary statistics from independent set of European ancestry individuals. We report a significant association between elevated DBP and the genetic risk of PrC (ß (SE)=0.066 (0.017), P-value=9.64×10^(-5)), as well as between CrC PGS and both, lower SBP (ß (SE)=-0.10 [0.029], P-value=3.83×10^(-4))) and lower DBP (ß (SE)=-0.055 [0.017], P-value=1.05×10^(-3)). Our analysis highlights two nominally significant relationships for individuals with genetic predisposition to elevated SBP leading to higher risk of KidC (OR [95%CI]=1.04 [1.0039-1.087], P-value=2.82×10^(-2)) and PrC (OR [95%CI]=1.02 [1.003-1.041], P-value=2.22×10^(-2)). Conclusion Using comorbidPGS, we underscore mechanistic relationships between blood pressure regulation and susceptibility to three comorbid malignancies. This package offers valuable means to evaluate shared genetic susceptibility between (cor)related phenotypes through polygenic scores.
RESUMO
Obesity and type 2 diabetes (T2D) are associated with increased risk of pancreatic cancer. Here we assessed the relationship between pancreatic cancer and two distinct measures of obesity, namely total adiposity, using BMI, versus abdominal adiposity, using BMI adjusted waist-to-hip ratio (WHRadjBMI) by utilising polygenic scores (PGS) and Mendelian randomisation (MR) analyses. We constructed z-score weighted PGS for BMI and WHRadjBMI using publicly available data and tested for their association with pancreatic cancer defined in UK biobank (UKBB). Using publicly available summary statistics, we then performed bi-directional MR analyses between the two obesity traits and pancreatic cancer. PGSBMI was significantly (multiple testing-corrected) associated with pancreatic cancer (OR[95%CI] = 1.0804[1.025-1.14], P = 0.0037). The significance of association declined after T2D adjustment (OR[95%CI] = 1.073[1.018-1.13], P = 0.00904). PGSWHRadjBMI association with pancreatic cancer was at the margin of statistical significance (OR[95%CI] = 1.047[0.99-1.104], P = 0.086). T2D adjustment effectively lost any suggestive association of PGSWHRadjBMI with pancreatic cancer (OR[95%CI] = 1.039[0.99-1.097], P = 0.14). MR analyses showed a nominally significant causal effect of WHRadjBMI on pancreatic cancer (OR[95%CI] = 1.00095[1.00011-1.0018], P = 0.027) but not for BMI on pancreatic cancer. Overall, we show that abdominal adiposity measured using WHRadjBMI, may be a more important causal risk factor for pancreatic cancer compared to total adiposity, with T2D being a potential driver of this relationship.