NEW YORK — Both rare and common genetic variants associated with disease contribute to a decrease in healthy life years, though with different levels of effect, a new analysis has found.
"We noted that there is no way of uniformly comparing how 'serious' different genetic risk factors are in terms of one's overall health," first author Sakari Jukarainen, a postdoc at the University of Helsinki, said in an email. "Inspired by the previous epidemiological work on modifiable risk factors by the Global Burden of Disease study, we thought that a similar framework could be implemented for genetic risk factors as well."
The researchers adapted the approach used by that study to consider the influence of both common and rare genetic variants on healthy life. In their study, which appeared in Nature Medicine on Monday, they combined data on disability-adjusted life years (DALYs) with genetic association data from more than 735,000 individuals from the FinnGen and UK Biobank studies. DALY is a metric of disease burden that considers both decreased quality of life and premature death due to a disease, where one DALY is equivalent to the loss of one year of healthy life.
While the presence of disease-linked common variants did influence the length of disability-free life, their effects were generally small at the individual level. For instance, carrying one copy of a missense variant in LPA was linked to 1.18 attributable DALYs, or the loss of more than a year of healthy life, mostly through the variant's influence on risk of ischemic heart disease. Additionally, a noncoding variant near POU5F1B was linked to 0.54 DALYs through its role in prostate cancer.
Likewise, harboring the most deleterious Alzheimer's disease haplotype, Apo-ε4/ε4, rather than the common Apo-ε3/ε3 haplotype, was linked a loss of about a year and a half of healthy life.
But at the population level, the effects of common variants could be high. Within the Finnish cohort, the researchers estimated how many healthy life years would be gained per year per 100,000 people if the minor alleles were not present in the population. The loss of the common variant rs7859727, affecting CDKN2B-CDKN2A, they found, would lead to the largest gain in healthy years — 447 years — as it is involved in ischemic heart disease and is present at a high frequency in Finns.
"Some of the most impactful common variants had similar effects at the population level compared to important modifiable risk factors such as diet high in sodium or low physical activity," Jukarainen said, noting that this level of effect was unexpected.
Rare genetic variants, meanwhile, had a greater effect at the individual level. The presence of one loss-of-function variant in BRCA1 was associated with the loss of about four years of healthy life, for example, due to its effects on breast and ovarian cancer. Variants in other genes like LDLR, BRCA2, MYBPC3, and MLH1 also reduced the number of years of healthy life. At the population level, variants in BRCA2 lead to 21 yearly population DALYs per 100,000 people.
The researchers also examined how polygenic risk scores for various conditions affected quality of life. Being in the top 10 percent risk group for multisite chronic pain through a PRS was linked to the loss of 3.63 years of healthy life, through effects on low back pain, ischemic heart disease, substance abuse disorder, COPD, depression, and neck pain.
These findings suggested to the researchers that genetic risk factors can account for a portion of healthy life years lost.
"Data from our study can be used to prioritize possible genetically informed interventions such as screening of genetic risk or targeted lifestyle interventions," Jukarainen said. But he noted that "what these interventions could be, and for which genetic risk factors, our study cannot say."