Combined Utility of 25 Disease and Risk Factor Polygenic Risk Scores for Stratifying Risk of All-Cause Mortality

Allison Meisner, Prosenjit Kundu, Yan Dora Zhang, Lauren V. Lan, Sungwon Kim, Disha Ghandwani, Parichoy Pal Choudhury, Sonja I. Berndt, Neal D. Freedman, Montserrat Garcia-Closas, Nilanjan Chatterjee

Research output: Contribution to journalArticlepeer-review

Abstract

While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated with all-cause mortality in independent data within the UK Biobank: the estimated hazard ratios per standard deviation were 1.10 (95% confidence interval: 1.05, 1.16) and 1.15 (1.10, 1.19) for women and men, respectively. Differences in life expectancy between the top and bottom 5% of the cPRS were estimated to be 4.79 (1.76, 7.81) years and 6.75 (4.16, 9.35) years for women and men, respectively. These associations were substantially attenuated after adjusting for non-genetic mortality risk factors measured at study entry (i.e., middle age for most participants). The cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors.

Original languageEnglish (US)
Pages (from-to)418-431
Number of pages14
JournalAmerican journal of human genetics
Volume107
Issue number3
DOIs
StatePublished - Sep 3 2020

Keywords

  • all-cause mortality
  • cause-specific mortality
  • genetic risk stratification
  • genome-wide association studies
  • lifestyle modification
  • polygenic risk scores

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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