comorbidPGS: An R Package Assessing Shared Predisposition between Phenotypes Using Polygenic Scores.

IF 1.1 4区生物学 Q4 GENETICS & HEREDITY Human Heredity Pub Date : 2024-01-01 Epub Date: 2024-05-13 DOI:10.1159/000539325

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

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Abstract

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.

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comorbidPGS：使用多基因评分评估表型之间共同易感性的 R 软件包。

导言：多基因评分（PGS）是一种有价值的方法，用于评估特定结果的估计遗传责任或导致数量性状的遗传变异。虽然 PRS 被广泛应用于复杂性状，但其在揭示表型之间的共同遗传易感性（即当遗传变异影响不止一种表型时）方面的应用仍然有限。方法我们开发了一个 R 软件包 comorbidPGS，它有助于利用 PGS 系统地评估（相关）表型之间的共享遗传效应。comorbidPGS 软件包将一组单核苷酸多态性（SNPs）及其对原始表型（Po）的既定影响作为输入，称为 Po-PGS。它能生成 Po-PGS 对目标表型（Pt）影响的综合摘要，并具有可定制的图形功能。结果我们利用欧洲血统的英国生物库个体和独立的欧洲血统个体集的 GWAS 元分析汇总统计数据，应用 comorbidPGS 研究了定义血压升高的表型（收缩压，SBP；舒张压，DBP；脉压，PP）和几种癌症（乳腺癌，BrC；胰腺癌，PanC；肾癌，KidC；前列腺癌，PrC；结直肠癌，CrC）之间的共同遗传易感性。我们报告了 DBP 升高与 PrC 遗传风险之间的显着关联（β (SE)=0.066 (0.017)，P 值=9.64×10^（-5）），以及 CrC PGS 与较低 SBP（β (SE)=-0.10 [0.029]，P-value=3.83×10^（-4））和较低 DBP（β (SE)=-0.055 [0.017]，P-value=1.05×10^（-3））之间的关系。）我们的分析显示，具有 SBP 升高遗传易感性的个体会导致更高的 KidC 风险（OR [95%CI]=1.04 [1.0039-1.087]，P 值=2.82×10^(-2)）和 PrC 风险（OR [95%CI]=1.02 [1.003-1.041]，P 值=2.22×10^(-2)）。结论我们利用 comorbidPGS 强调了血压调节与三种合并恶性肿瘤易感性之间的机理关系。该软件包为通过多基因评分评估（相关）表型之间的共同遗传易感性提供了宝贵的手段。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Heredity 生物-遗传学

CiteScore

2.50

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： Gathering original research reports and short communications from all over the world, ''Human Heredity'' is devoted to methodological and applied research on the genetics of human populations, association and linkage analysis, genetic mechanisms of disease, and new methods for statistical genetics, for example, analysis of rare variants and results from next generation sequencing. The value of this information to many branches of medicine is shown by the number of citations the journal receives in fields ranging from immunology and hematology to epidemiology and public health planning, and the fact that at least 50% of all ''Human Heredity'' papers are still cited more than 8 years after publication (according to ISI Journal Citation Reports). Special issues on methodological topics (such as ‘Consanguinity and Genomics’ in 2014; ‘Analyzing Rare Variants in Complex Diseases’ in 2012) or reviews of advances in particular fields (‘Genetic Diversity in European Populations: Evolutionary Evidence and Medical Implications’ in 2014; ‘Genes and the Environment in Obesity’ in 2013) are published every year. Renowned experts in the field are invited to contribute to these special issues.