130: Genetics + CRISPR to Map Obesity and Fat Distribution

Baya NA et al., The American Journal of Human Genetics - This episode summarizes a multi-modal study that integrates exome sequencing in 402,375 UK Biobank participants with CRISPR knockdown in human white adipocytes to nominate genes and pathways that alter overall adiposity and fat distribution. Key terms: obesity, fat distribution, exome sequencing, CRISPR knockdown, adipocytes. Study Highlights:The authors performed rare-variant (MAF<1%) exome-wide association testing across nine obesity- and depot-specific fat traits in 402,375 European-ancestry UK Biobank participants, identifying 19 exome-wide significant genes and 50 additional genes at FDR≤1% (69 total). They prioritized 14 genes for CRISPR-Cas9 knockdown in a human white adipocyte cell line and measured lipid accumulation with BODIPY staining and high-content imaging. Knockdown of PPARG and SLTM significantly decreased lipid accumulation, while COL5A3 knockdown increased it; EXOC7 and TRIP10 had nominal increases. Integrating population genetics, allelic series, longitudinal age-of-onset, and transcriptomics highlighted candidate therapeutic avenues to modulate adiposity and fat distribution. Conclusion:Combining large-scale human genetic association with targeted functional screens in human adipocytes identifies high-confidence genes and mechanisms—such as adipogenesis regulation and extracellular matrix components—that can inform therapeutic strategies to alter body fat amount and distribution. Music:Enjoy the music based on this article at the end of the episode. Article title:Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution First author:Baya NA Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2025.08.013 Reference:Baya NA, SurErdem I, Venkatesh SS, et al.; Claussnitzer M, Palmer DS, Lindgren CM. Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution. The American Journal of Human Genetics. 2025;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:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/combining-evidence-from-human-genetic-and-functional-screens-to-identify-pathways-altering-obesity-and-fat-distribution QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-07. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections describing UK Biobank exome sequencing and nine fat-trait phenotypes, identification of candidate genes, CRISPR-Cas9 functional validation in human white adipocytes, key gene findings (PPARG, SLTM, COL5A3), monotonic dose–response relationships, and obesity-age-onset analyses.- transcript topics: UK Biobank exome sequencing design and nine fat-related traits; Rare-variant gene-level associations and PoPS integration; CRISPR-Cas9 knockdown in human white adipose tissue cells and BODIPY lipid readouts; Key genes PPARG, SLTM, COL5A3 and their lipid-accumulation effects; Monotonic allelic series and dose-response relationships; Longitudinal obesity age-of-onset analyses (MC4R, SLTM) QC Summary:- factual score: 10/10- metadata score: 10/10- sup...