Sequence variants associated with BMI affect disease risk through BMI itself.

Area of Science:

• Genetics
• Epidemiology
• Metabolic Diseases

Background:

• Mendelian Randomization (MR) studies link Body Mass Index (BMI) to numerous diseases.
• The precise mediating pathways for these associations remain incompletely understood.

Purpose of the Study:

• To investigate whether genetic predisposition to higher BMI increases disease risk solely through BMI or via other biological mechanisms.
• To differentiate direct genetic effects on disease from those mediated by BMI.

Main Methods:

• Utilized MR with genetic risk scores for BMI in large population datasets (Icelandic and UK Biobank).
• Examined associations between BMI genetic risk score and various disease outcomes, both unadjusted and conditioned on measured BMI.
• Assessed attenuation of disease risk associations after accounting for BMI's effect.

Main Results:

• Associations between BMI genetic risk score and diseases including fatty liver disease, glucose intolerance, and knee replacement were fully attenuated when conditioned on BMI.
• Significant attenuation was also observed for type 2 diabetes, heart failure, myocardial infarction, atrial fibrillation, and hip replacement.
• Partial attenuation was noted for chronic kidney disease and stroke, with some variability.

Conclusions:

• The findings strongly suggest that the majority of disease risks associated with BMI-related genetic variants are mediated through BMI itself.
• This highlights the potential of BMI reduction as a therapeutic strategy for a wide range of obesity-related conditions.
• Residual effects warrant further investigation into potential pleiotropy, temporal changes in BMI, or other confounding factors.