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Genome-wide pleiotropy analysis identifies novel blood pressure variants and improves its polygenic risk scores

Xiaofeng Zhu1, Luke Zhu2, Heming Wang3

  • 1Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.

Genetic Epidemiology
|January 6, 2022
PubMed

Insights

This study developed a new genetic risk score (GRS) using pleiotropic variants to better predict blood pressure (BP) and cardiovascular disease (CVD) risk. The enhanced GRS significantly improved heritability and prediction accuracy for hypertension and CVD.

Area of Science:

  • Genetics
  • Cardiovascular Disease Research
  • Biostatistics

Background:

  • Systolic and diastolic blood pressure (S/DBP) are key modifiable risk factors for cardiovascular disease (CVD).
  • Understanding genetic contributions to blood pressure regulation is crucial for developing effective prevention and treatment strategies.
  • Mendelian Randomization (MR) and pleiotropy analyses offer powerful tools to investigate causal relationships between genetic variants and complex traits.

Purpose of the Study:

  • To perform a bidirectional Mendelian Randomization (MR) and horizontal pleiotropy analysis for S/DBP.
  • To construct a composite genetic risk score (GRS) incorporating pleiotropic variants.
  • To evaluate the enhanced heritability and predictive power of the composite GRS for hypertension and CVD.

Main Methods:

  • Utilized summary statistics from the UK Biobank (UKB)-International Consortium for Blood Pressure (ICBP) genome-wide association study (GWAS).
  • Conducted bidirectional MR and horizontal pleiotropy analysis to identify relevant genetic variants.
  • Constructed a composite GRS by including identified pleiotropic variants and assessed its performance using Nagelkerke's R².
  • Replicated novel findings using summary statistics from the Million Veteran Program (MVP) study.

Main Results:

  • The composite GRS demonstrated significantly greater heritability for BP traits (1.11-3.26 fold).
  • The GRS substantially increased prediction accuracy for hypertension (1.09-fold) and CVD (2.01-fold) as measured by Nagelkerke's R².
  • Replicated 118 novel BP horizontal pleiotropic variants, including 18 novel BP loci, in the MVP study.
  • A meta-analysis identified an additional 219 novel BP signals and 40 novel loci.

Conclusions:

  • Incorporating pleiotropic variants into a GRS enhances its ability to capture BP heritability and predict hypertension and CVD risk.
  • This study validates novel genetic variants associated with blood pressure regulation.
  • The developed method offers a novel approach for constructing GRSs for complex diseases by leveraging pleiotropic variants.

Keywords:
Mendelian Randomizationgene-age interactiongenetic risk scorepleiotropy

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