Bridging the variant-to – function gap in type 2 diabetes: advances and challenges – Published online 22/11/2025

Adam G Maynard, Raghav Bhardwaj, Thouis R. Jones, Melina Claussnitzer

Transitioning from the era of genetic discovery to mechanistic understanding represents a grand challenge in metabolic precision medicine. Deciphering how genetic variants contribute to disease risk, particularly those in non-coding regions, constitutes the variant-to-function (V2F) problem central to the future of human genetics. In this issue, Maynard et al (https://doi.org/10.1007/s00125-025-06600-6) trace key V2F discoveries that are advancing our understanding of how variants influence molecular mechanisms underlying type 2 diabetes. They examine progress across disease-relevant tissues—pancreatic islets, adipose tissue, liver and muscle—detailing complexities involved in linking non-coding variants to effector genes and biological pathways driving disease. The authors also explore emerging experimental and computational technologies accelerating V2F research, including scalable CRISPR-based screens, single-cell multi-omics and machine learning approaches, while addressing ongoing challenges such as tissue heterogeneity and context-dependent regulation. The authors conclude that these developments provide a foundation for precision medicine strategies tailored to the molecular heterogeneity underlying type 2 diabetes. The figures from this review are available as a downloadable slideset.

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