Written by Peter Liu
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An XWAS-GWAS* analysis in ~500,000 UK Biobank participants identified 25 environmental exposures linked to aging, mortality, and common diseases, showing more mortality variance than genetic risk scores.
*XWAS means exposome-wide association study (everything a person is exposed to in the environment); GWAS means genome-wide association study.
Nature or nurture? Now we know…
Large-scale, genome-wide statistical methods now enable hypothesis-free discovery of meaningful associations between genetic and environmental factors shaping patient outcomes. A recent XWAS analysis of UK Biobank data (n=492,567) identified 25 environmental exposures significantly associated with biological aging and all-cause mortality. These exposures were then compared to age and genetic risk to determine which best explained variation in mortality and common diseases.
On mortality and aging:
The 25 exposures most strongly associated with mortality included current smoking, council housing (subsidized housing) vs. home ownership, and frequent fatigue as negative factors; while protective factors included higher income, employment, non-white ethnicity, physical activity, and cohabitation with a partner. These exposures explained 17% of mortality variation, whereas polygenic risk scores for 22 diseases explained less than 2%. Biological age was assessed using proteomic (phenotypic) data rather than chronological age.
On environmental and genetic contribution to disease:
The study then evaluated how actual age, environmental exposure (through these 25 aging-related exposures), and genetic risk (characterized by polygenic risk scores) accounted for occurrence of 25 diseases and 3 disease risk factors. For most diseases, these three components accounted for over 50% of the variation in the population. Diseases more influenced by environmental exposures included COPD, liver disease, lung cancer, rheumatoid arthritis, and ischemic heart disease. In contrast, breast, prostate, and ovarian cancers, as well as dementia, were more strongly associated with genetic risk.
How does this change my practice?
Overall, this study applies a clever and interesting research technique (the XWAS study) to highly relevant clinical topics on aging, death, and age-related disease. While the results are theoretical, they offer several opportunities for clinicians. First, it is empowering for patients and clinicians to know that most medical risk is environmental and modifiable, with smoking cessation, increased physical activity, and increased social participation. Conversely, it is also sometimes helpful to know that the onset of certain diseases are genetic and not the patient’s fault. Finally, the study reinforces the importance of optimizing social determinants of health for patients.
Source
Integrating the environmental and genetic architectures of aging and mortality. Nat Med. 2025 Mar;31(3):1016-1025. doi: 10.1038/s41591-024-03483-9. Epub 2025 Feb 19. PMID: 39972219
