Discussion
Using human data, we provide genetic evidence supporting the notion that chronically elevated GDF15 levels increase BMI. There was no genetic evidence to support bi-directional effects, or that chronically elevated GDF15 levels directly affect liability to type 2 diabetes. Our results contrast the BMI lowering effects of an acute increase in GDF15 levels observed after metformin use2. One possible explanation for this discrepancy is that chronic elevation of circulating GDF15 levels leads to desensitization of the GDF15 receptor and reduced signaling8.
The use of both colocalization and Mendelian randomization in this study provide complementary evidence supporting causal effects of chronically elevated GDF15 levels on BMI. As genetic variants are randomly allocated at conception, the Mendelian randomization paradigm is less susceptible to the confounding and reverse causation that that can hinder causal inference in observational studies. As a limitation of this work, the genetic associations were derived from individuals of European ancestries, and therefore our results may not generalize to other ethnic groups.
In conclusion, this genetic analysis found robust evidence to support that, in contrast to acute elevations in GDF15 levels, chronically elevated GDF15 levels increase BMI. These findings may be used to inform the design of pharmacological strategies aimed at targeting GDF15 for weight loss.
References
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Figure. Colocalization plot of genetic associations for circulating growth differentiation factor 15 levels and body mass index within ±10 kb of GDF15 gene. LD = linkage disequilibriumr2 with rs16982345, the variant identified as the most likely shared causal variant.