Genetics and unhealthy old age
Genetic risk factors of diseases reduce the duration of a healthy life
Elena Kleshchenko, PCR.news
"We noted that there is no way to uniformly compare how 'serious' different genetic risk factors are in terms of overall health," first author Sakari Yukarainen, a postdoc at the University of Helsinki, replied in an email to GenomeWeb. — Inspired by previous epidemiological work on modifiable risk factors within the Global Burden of Disease (an international study that analyzes 286 causes of death, 369 diseases and injuries, and 87 risk factors in 204 countries and territories. — PCR.NEWS), we thought that a similar structure could be implemented for genetic risk factors."
The researchers adapted the approach used in the Global Burden of Disease to assess the impact of common and rare genetic variants on healthy life expectancy. They combined data on disability-adjusted life years (DALYs) with data from more than 735,000 people from FinnGen and UK Biobank studies. The participants of both projects, whose genetic data are known, have been observed for decades. The DALY indicator is the years of healthy life potentially lost due to premature death and disability. It takes into account both a decrease in the quality of life and death due to illness.
The authors examined 80 non-communicable diseases, accounting for 83.1% of the total DALYs of all non-communicable diseases in Finland in 2019, as well as 1,044 common genetic variants, 9 rare variants, 74 HLA alleles and 30 polygenic risk assessments.
Although the presence of common variants associated with the disease did affect life expectancy without disability, the impact at the individual level was usually small. For example, carrying one copy of the missense variant in the LPA gene is associated with 1.18 DALY, that is, the loss of just over a year of healthy life, mainly due to the effect of this variant on the risk of coronary heart disease. A non-coding variant next to the POU5F1B gene leads to 0.54 DALY due to its role in the development of prostate cancer.
The most dangerous variant associated with Alzheimer's disease, Apo-e4/e4, was associated with the loss of about one and a half years of healthy life compared to Apo-e3/e3.
At the population level, the impact of common variants can be very high. In the Finnish cohort, researchers calculated how many years of healthy life could be added per 100,000 people per year if minor alleles disappeared from the population. The loss of the common variant rs7859727, which affects CDKN2B-CDKN2A, would lead to the greatest increase — 447 healthy years — since this variant is associated with coronary heart disease and is present with a high frequency in Finns.
Yukarainen stressed that they did not expect such a significant result: "Some of the most effective common variants had effects at the population level comparable in significance to important modifiable risk factors, such as a high-sodium diet or low physical activity."
As for rare genetic variants, their effect on the individual level was more impressive. One variant with loss of function in BRCA1 was associated with the loss of approximately four years of healthy life, in particular due to its effect on breast and ovarian cancer. Variants of many other genes, such as LDLR, BRCA2, MYBPC3 and MLH1, were also significant. At the population level, variants in BRCA2 result in 21 DALY per 100,000 people.
The researchers also found out how polygenic risk indicators for various conditions affect the quality of life. Getting into the 10% risk group for multi-focal chronic pain was associated with the loss of 3.63 years of healthy life due to lower back pain, coronary heart disease, substance abuse, chronic obstructive pulmonary disease, depression and neck pain.
According to Yukarainen, the results of such studies can be used to prioritize measures such as genetic risk screening or lifestyle correction, but it is still difficult to give specific recommendations.
Article by Jukarainen et al. Genetic risk factors have a substantial impact on healthy life years published in the journal Nature Medicine.
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