共病多基因风险评分：一个使用多基因评分评估表型间共享易感性的R软件包。

Pascat Vincent, Zudina Liudmila, Ulrich Anna, Maina Jared G, Kaakinen Marika, Pupko Igor, Bonnefond Amélie, Demirkan Ayse, Balkhiyarova Zhanna, Froguel Philippe, Prokopenko Inga

INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France.

University of Lille, Lille University Hospital, Lille, France.

Hum Hered. 2024;89(1):60-70. doi: 10.1159/000539325. Epub 2024 May 13.

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 polygenic risk scores 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 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) and several cancers (breast cancer; 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 (β [SE] = 0.066 [0.017], p value = 9.64 × 10-5), as well as between CrC PGS and both, lower SBP (β [SE] = -0.10 [0.029], p value = 3.83 × 10-4) and lower DBP (β [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.

引言

多基因评分（PGS）是一种评估对特定结果的估计遗传易感性或对数量性状有贡献的遗传变异性的有价值方法。虽然多基因风险评分广泛用于复杂性状，但它们在揭示表型之间共享的遗传易感性方面的应用仍然有限，即当遗传变异影响多个表型时。

方法

我们开发了一个R包comorbidPGS，它有助于使用PGS对（相关）表型之间共享的遗传效应进行系统评估。comorbidPGS包将一组单核苷酸多态性及其对原始表型（Po）已确定的效应作为输入，称为Po-PGS。它生成Po-PGS对目标表型（Pt）效应的全面总结，并具有可定制的图形特征。

结果

我们应用comorbidPGS，使用欧洲血统的英国生物银行个体以及来自独立欧洲血统个体集的GWAS荟萃分析汇总统计数据，来研究定义高血压的表型（收缩压，SBP；舒张压，DBP；脉压）与几种癌症（乳腺癌；胰腺癌，PanC；肾癌，KidC；前列腺癌，PrC；结直肠癌，CrC）之间共享的遗传易感性。我们报告DBP升高与PrC的遗传风险之间存在显著关联（β[标准误]=0.066[0.017]，p值=9.64×10⁻⁵），以及CrC PGS与较低的SBP（β[标准误]= -0.10[0.029]，p值=3.83×10⁻⁴）和较低的DBP（β[标准误]= -0.055[0.017]，p值=1.05×10⁻³）均存在显著关联。我们的分析突出了两个名义上显著的关系，即具有SBP升高遗传易感性的个体患KidC（比值比[95%置信区间]=1.04[1.0039 - 1.087]，p值=2.82×10⁻²）和PrC（比值比[95%置信区间]=1.02[1.003 - 1.041]，p值=2.22×10⁻²）的风险更高。