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All-Cause Mortality Associated With New Sex-Specific Polygenic Risk Scores

NEW YORK – A team led by researchers at Johns Hopkins University has combined polygenic risk scores (PRS) for more than two dozen conditions or mortality-related traits into a composite PRS (cPRS) for all-cause mortality that appears to show promise for distinguishing individuals with particularly long or short lifespans.

"The cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors," senior and corresponding author Nilanjan Chatterjee, a biostatistics and oncology researcher at the Johns Hopkins Bloomberg School of Public Health and the Johns Hopkins University School of Medicine, and his colleagues wrote for a paper appearing in the American Journal of Human Genetics on Wednesday.

Starting with data on the most common causes of death in Caucasians over 40 years old in the US in 2017, the researchers combined polygenic risk scores (PRS) for 13 conditions — ranging from heart disease or hypertension to pancreatic cancer or Parkinson's disease — and a dozen more mortality-related features such as body mass index, blood triglyceride levels, and smoking or alcohol use to establish biological sex-specific cPRS for 337,138 genotyped individuals from  the UK Biobank, including more than 13,600 deceased participants.

After training the cPRSs with data for 120,719 women and 104,037 men assessed through the UK Biobank project, they found that the scores showed modest ties to all-cause mortality in another 60,308 female and 52,074 male participants in that study, while PRS linked to specific traits or diseases each remained moderately or strongly linked to those conditions.

"[O]ur results suggest that by combining knowledge gained from GWAS of complex traits, it may be possible to identify individuals who are expected to live substantially longer or shorter," the authors reported. "In light of the ethical repercussions of using genetics to make predictions regarding an individual's life course prior to or at birth, we argue that the cPRS may be most useful for counseling those in early adulthood about their genetic risk."

In women, the team found that life expectancy differed by close to five years between individuals in the top and bottom 5 percent on the female-specific cPRS, whereas in men, life expectancy differed by an estimated 6.8 years.

The researchers noted that mortality-related traits and behaviors could modify the predictive capabilities of the cPRS over time, suggesting that the composite risk scores have more pronounced associations with all-cause mortality in younger individuals, with waning abilities to predict enhanced or diminished lifespan as individuals age.

"[T]he results of our analysis highlight the importance of considering genetic risk in the context of clinical risk factors measured in adulthood," the authors wrote, adding that cPRS "may be useful in advising patients on the importance of certain lifestyle choices associated with mortality risk."

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