April 8, 2026

expert reaction to paper about genetic predictors of GLP1 receptor agonist weight loss and side effects

A study published in Nature looks at genetic predictors of GLP-1 medication weight loss and side effects. 

Dr Marie Spreckley, Research Programme Manager, University of Cambridge, said:

“This is a large genome-wide association study (n≈27,900) examining variability in weight loss and side effects among people taking GLP-1 receptor agonists, using 23andMe self-reported data. The authors identify a missense variant in the GLP1 receptor gene (rs10305420) associated with slightly greater weight loss, corresponding to around 0.76 kg additional loss per allele, alongside variants linked to nausea and vomiting, particularly for tirzepatide via GIPR. 

“In terms of what this study adds, it provides biologically plausible evidence that variation in the drug target itself (GLP1R) and related pathways (GIPR) contributes to inter-individual variability in response. However, the magnitude of these genetic effects is small in clinical terms. In clinical trials, typical weight loss with these medications is often in the range of around 10-15%, so a difference of less than 1kg per allele is modest.

“Importantly, non-genetic factors such as sex, drug type, dose, and duration appear to explain a substantially larger proportion of variability. The authors’ model suggests that most of the explained variance comes from these factors, with genetics adding only a modest incremental contribution. 

“In terms of quality, this is a well-conducted GWAS with appropriate statistical thresholds, biologically coherent findings, and replication in an external cohort, although this was not consistent across all datasets. The fact that the identified variants map directly to the drug targets strengthens the biological credibility of the findings.

“There are, however, important limitations. The primary dataset relies on self-reported weight, treatment duration, and side effects, which introduces measurement error and potential reporting bias. The authors show that self-reported weight loss was substantially greater than that recorded in linked electronic health records (approximately -11.8% vs -5.8%), highlighting systematic differences between data sources. 

“The cohort is also not fully representative, being predominantly female and largely of European ancestry, which limits generalisability. In addition, the median treatment duration was relatively short (around 8 months), so longer-term outcomes are not captured. 

“In terms of how this fits with the wider evidence, it reinforces that while there is substantial variability in response to GLP-1 therapies, genetics is only one part of a much more complex picture. Behavioural, clinical, and treatment-related factors remain the dominant drivers of outcomes.

“Overall, this is an important step towards understanding variability and the potential for future precision approaches, but the effects are modest and the evidence is not yet sufficient to support using genetic information to guide treatment decisions in routine clinical practice.

‘Genetic predictors of GLP1 receptor agonist weight loss and side effects by Qiaojuan Jane Su et al. was published in Nature at 16:00 UK Time Wednesday the 8^th April 2026. 

DOI: 10.1038/s41586-026-10330-z

Declared interests

Dr Marie Spreckley: “I am a postdoctoral researcher at the University of Cambridge working on obesity, incretin-based therapies and nutrition. I have no personal financial relationships with manufacturers of GLP-1 receptor agonists and have received no industry funding.”