Fantastic work, really interesting to see MC4R extend its role beyond apptetite. We’ve also found surprisingly frequent POMC risk and MC4R protective variants in the Estonian population; We’ll check if retrospective semaglutide data from the Estonian Biobank align with the tirzepatide findings :)

7/7 Take-home: even in well-studied European populations, there’s hidden biology waiting to be found. Using population-specific imputation panels lets you see uncommon and rare variants that global panels often miss.
rdcu.be/eJ0ge #GWAS #genetics #obesity @natcomms.nature.com

6/7 Also also: an intronic protective ADGRL3 variant, located near CTCF sites. ADGRL3 gene is better known for its role in neurodevelopment and ADHD and is for first time linked to BMI; it has intriguing possibly has ties to incretin biology (GIP). Worth a deeper functional look!

5/7 We also found a few noteworthy novel protective coding hits: PTPRT:p.Arg1384His associates with lower BMI and points to the leptin–melanocortin axis. As phosphatases are considered druggable, this could be a potential anti-obesity target to explore.

4/7 An almost identical variant has previously been found in labrador retrievers, which leads to increased food motivation and body weight (@stephenorahilly.bsky.social ). We can hypothesize that this variant leads to similar traits in humans as well.

3/7 Highlight: a stop-gain POMC variant (p.Glu206*) that truncates β-MSH & β-endorphin. And it's surprisingly common: >1,700 heterozygous carriers in Estonia (~0.85% of Estonian Biobank participants); likely tens of thousands across N/E Europe.

2/7 We used the youngest available adult BMI per person to amplify genetic signal (median age ~42, which is about 15–20 years younger than other similar biobank cohorts). Result: 214 genome-wide loci in EstBB, mostly neurological pathways, many known, plus some fresh ones.

Ega jõua ka kõike kõikjal ja korraga :)