Study reveals that BMI plays a crucial role in disease development, with genetic links to conditions like fatty liver disease disappearing when BMI is considered.
Study: Sequence variants associated with BMI affect disease risk through BMI itself. Image Credit: Halfpoint/Shutterstock.com
In a recent study published in Nature Communications, a team of scientists from Iceland explored whether genetic variants linked to body mass index (BMI) could influence disease risk directly through BMI or through other mechanisms.
They examined study populations from Iceland and the United Kingdom (UK) to explore the association between BMI-related genetic factors and the risk of conditions such as type 2 diabetes, myocardial infarction, osteoarthritis, and stroke.
Background
Body mass index is beginning to emerge as a major risk factor for several chronic diseases, including type 2 diabetes, cardiovascular diseases, and osteoarthritis. Higher BMI contributes to conditions related to fat accumulation and metabolic stress, such as fatty liver disease and glucose intolerance, as well as biomechanical conditions, such as knee osteoarthritis.
Previous studies have identified BMI to be a highly polygenic trait, with specific genetic variants contributing to its increase. Genome-wide association studies (GWAS) have identified hundreds of BMI-related variants that contribute partially to BMI variability among individuals.
Furthermore, Mendelian randomization analyses can be used to assess if specific genetic markers influence disease risk solely through BMI. However, this relationship is complex, as some genetic markers associated with BMI may also affect disease risk through other pathways, as seen in pleiotropy.
About the study
In the present study, the scientists used data from two cohorts — one from the population of Iceland and the other consisting of participants from the UK Biobank — to examine the association between BMI-related genetic variants and disease risk.
Height and weight measures of the participants, adjusted for age and sex and then averaged across multiple measurements, were used to calculate the BMI. The researchers selected 665 independent genetic variants associated with BMI to create BMI genetic risk scores (BMI-GRS), ensuring that the variants were independently associated with BMI by limiting linkage disequilibrium. Outlier variants with atypical associations with disease risk were removed to reduce potential bias.
To test the hypothesis that BMI mediates disease risk, the scientists conducted a mediation analysis on disease outcomes such as type 2 diabetes, heart failure, and myocardial infarction. The BMI-GRS was associated with these diseases in both cohorts. Then, by controlling for actual BMI, they assessed the extent to which BMI explained these associations.
For quality control, repeated BMI measurements were assessed to ensure stability over time. This was done by calculating BMI correlations over five-year intervals in Icelandic participants. The analyses were also stratified by sex to examine potential sex-specific effects on disease risk.
Results
The study found that BMI-GRS or the BMI genetic risk scores were significantly associated with increased disease risk for multiple conditions, notably type 2 diabetes, fatty liver disease, and osteoarthritis. When the analyses were adjusted for measured BMI, the disease associations with BMI-GRS were found to diminish, suggesting that much of the genetic risk is mediated through BMI.
For some conditions, including knee replacement and glucose intolerance, the BMI-GRS association was completely attenuated after adjusting for BMI, indicating that BMI itself mediated these risks. For other diseases, such as type 2 diabetes and heart failure, the risk was partially mediated by BMI, with residual associations suggesting that there could be additional contributing factors.
In both Icelandic and UK Biobank data, the attenuation of BMI-GRS effects after adjusting for BMI was consistent. However, differences were observed in the degree of mediation for conditions such as chronic kidney disease. This suggested that while BMI accounts for much of the genetic risk, some associations are independent of BMI, possibly due to pleiotropic genetic effects or other unmeasured influences.
Additionally, stratification of the analyses by sex revealed generally consistent results, with a notable exception in myocardial infarction risk, which showed residual association in males but not in females. This suggested potential sex-based differences in the way BMI-related genetic factors influenced certain diseases.
Conclusions
Overall, the findings indicated that BMI was a primary mediator of the relationship between BMI-associated genetic variants and disease risk, especially for metabolic and mechanical conditions, such as type 2 diabetes and osteoarthritis, respectively.
However, certain conditions retained residual associations with other unmeasured factors, indicating the need for further investigation into other contributing genetic or lifestyle factors beyond BMI.
Journal reference:
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Einarsson, G., Thorleifsson, G., Steinthorsdottir, V., Zink, F., Helgason, H., Olafsdottir, T., Rognvaldsson, S., Tragante, V., Ulfarsson, Magnus O, Sveinbjornsson, G., Snaebjarnarson, Audunn S, Einarsson, H., Aegisdottir, Hildur M, Jonsdottir, G. A., Helgadottir, A., Gretarsdottir, S., Styrkarsdottir, U., Arnason, H. K., Bjarnason, R., & Sigurdsson, E. (2024). Sequence variants associated with BMI affect disease risk through BMI itself. Nature Communications, 15(1), 9335. doi:10.1038/s41467024535689, https://www.nature.com/articles/s41467-024-53568-9
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