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In a recent study published in Nature Medicine, researchers explored the genetic risk factors associated with various diseases to understand their impact on healthy life years.
The researchers estimated this impact using the metric disability-adjusted life years (DALYs), the healthy life years lost due to a deteriorating quality of life or premature death caused by a disease.
Studies investigating the association of genetic variants with disease risk have identified widespread pleiotropy, when one genetic variation influences two or more unrelated traits. The quantification of the impact of genetic risk factors on human health has been either limited to single disease studies or lacks comparable metrics other than lifespan.
Comparative risk assessments have examined the effect of modifiable exposures like sodium intake on overall health, but a systematic assessment of the impact of genetic risk factors is still lacking. A comprehensive evaluation of the influence of genetic risk factors on overall disease burden would be highly informative in implementing genetic screening and in vivo gene editing in providing targeted therapy to improve quality of life.
The present study used the data from two biobank studies, FinnGen and UK Biobank, and compiled genetic information from 735,748 individuals on 80 diseases. This was correlated with the DALY estimates from a 2019 Global Burden of Disease (GBD) study, which estimated the DALY ascribed to an exhaustive list of diseases and injuries for each country. The years lived with disability (YLDs), which indicate a reduced quality of life, and years of life lost (YLLs), indicating premature death due to disease or injury, are combined to calculate DALY.
To develop a standard for comparative risk assessment, the researchers ranked genetic risk factors according to their health impacts and associated them with modifiable risk factors. This approach provides a consistent metric to compare the health impacts of genetic risk variants across various diseases.
The results indicated that at an individual level, the rare genetic variants had a greater impact on DALYs than the common ones. Rare deleterious genetic variants related to cancers of the breast, ovaries, prostate, liver, colon, and rectum, as well as those for cardiomyopathy, myocarditis, and ischemic heart disease, have the highest impact on individual DALYs.
On the population level, these rare variants had a substantially lower impact on DALYs than the common variant due to their low frequencies in a population. A variant in the lipoprotein A (LPA) locus had the highest number of individual-level DALYs and is involved in ischemic heart disease and non-rheumatic valvular heart disease.
The common genetic variants that had a large impact on DALYs pertained to ischemic heart disease risk, dementia, prostate cancer, or type 2 diabetes. Since the number of DALYs for a disease is based on its prevalence, contribution to premature death, and its role in lowering the quality of life, common diseases have a higher population DALY since they result in a prolonged life with a disability or lead to premature mortality.
The authors also considered variants that affected intermediate risk factors, such as blood pressure and body mass index, while calculating DALYs. However, the variants with the high DALY scores correlated directly to the disease and not the intermediate risk factors.
One exception was the variant in the CHRNA5/A3/B4 gene cluster, which causes nicotine dependence. While an intermediate risk factor, this variant resulted in high DALY scores because of its role in lung cancer, vascular intestinal disorder, aortic aneurism, and chronic obstructive pulmonary disease.
The traits that contribute to PGS can be either cardiometabolic such as coronary heart disease or type 2 diabetes, or related to pain and addiction, which include substance dependence, lower back pain, multisite chronic pain, major depressive disorders, and smoking. The study found that being in the top 10% of PGS for multisite chronic pain had a large impact on the DALYs.
Overall, the results indicate that genetic risk factors can have a high impact on the number of healthy years lost due to reduced quality of life or premature death caused by a disease. The study revealed that some common disease-associated genetic variants have DALYs comparable to established modifiable risk factors such as sodium intake.
The stratification of genetic risk factors according to the health impacts can help prioritize treatments and interventions and reduce the impact of the disease on the quality of life. The authors also believe that while genetic risk factors are currently not modifiable, this information can be used to improve genetic screening and prioritize targets for in vivo gene editing.