️ Episode 130: Combining Evidence from Human Genetic and Functional Screens to Identify Pathways Altering Obesity and Fat Distribution

In this episode of PaperCast Base by Base, we explore a large-scale study that integrates genetic association testing with functional CRISPR experiments in human adipocytes to uncover mechanisms influencing obesity and body fat distribution. By analyzing data from more than 400,000 individuals in the UK Biobank and combining it with laboratory assays, the researchers highlight novel genetic contributors to lipid accumulation.

Study Highlights:
The study examined rare and common genetic variants across nine obesity-related and fat distribution traits, identifying 69 genes associated with overall adiposity or specific fat depots. Among these, 14 genes were selected for CRISPR knockdown experiments in human white adipose tissue cell lines. Knockdown of PPARG and SLTM significantly reduced lipid accumulation, while COL5A3 knockdown increased it. The results demonstrate how converging population genetics and in vitro evidence can pinpoint therapeutic targets for obesity and related conditions.

Conclusion:
This integrative approach suggests that targeting key genes regulating adipogenesis could open new therapeutic avenues for obesity and fat distribution disorders.

Reference:
Baya, N.A., Erdem, I.S., Venkatesh, S.S., Reibe, S., Charles, P.D., Navarro-Guerrero, E., Hill, B., Lassen, F.H., Claussnitzer, M., Palmer, D.S., & Lindgren, C.M. (2025). Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution. *The American Journal of Human Genetics*, 112, 1–22. https://doi.org/10.1016/j.ajhg.2025.08.013

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
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Keywords: obesity, fat distribution, exome sequencing, CRISPR, adipogenesis