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Bridging the variant-to-function gap in type 2 diabetes: advances and challenges
Adam G Maynard1,2, Raghav Bhardwaj1,2, Thouis R Jones1,2,3
1Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Diabetologia
|November 22, 2025
Summary
New strategies are linking genetic variants to specific gene functions, improving our understanding of type 2 diabetes mechanisms. This research helps bridge the gap between genetic discoveries and biological insights for precision medicine.
Area of Science:
- Genetics
- Metabolic Diseases
- Molecular Biology
Background:
- Type 2 diabetes affects over 530 million globally, with numbers projected to reach 1.3 billion by 2050.
- Genome-wide association studies identified over 1200 type 2 diabetes loci, but most risk variants are in non-coding regions, hindering biological interpretation and explaining limited heritability.
Purpose of the Study:
- To review advances in variant-to-function (V2F) strategies for linking non-coding genetic variants to molecular mechanisms in type 2 diabetes.
- To highlight V2F discoveries in key type 2 diabetes-related tissues and discuss emerging tools for precision medicine.
Main Methods:
- Fine-mapping
- Chromatin profiling
- Single-cell multi-omics
- Scalable CRISPR-based perturbation strategies
- Machine learning tools
Main Results:
- V2F strategies are beginning to link non-coding variants to effector genes, tissues, and molecular mechanisms.
- Specific examples include TCF7L2 in pancreatic beta cells, SLC16A11 and PNPLA3 in hepatocytes, and GLUT4 trafficking in adipocytes and muscle.
- A summary table of V2F discoveries and a discussion of emerging tools are provided.
Conclusions:
- Recent V2F advances are crucial for understanding the biological basis of type 2 diabetes genetic risk.
- These developments are essential for addressing disease heterogeneity and paving the way for precision medicine approaches.
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