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Polygenic background contributes to GCK-MODY clinical presentation and glycaemic variability.

Jacques Murray Leech1, Ankit M Arni1, V Kartik Chundru1

  • 1Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.

Diabetologia
|March 18, 2026
PubMed
Summary

Polygenic background interacts with GCK variants to influence glucokinase maturity-onset diabetes of the young (GCK-MODY) severity. This interaction affects clinical diagnosis and differs from HNF1A-MODY, emphasizing combined genetic factors in monogenic diseases.

Keywords:
DiabetesGenetic riskGeneticsGlucokinaseHbA1cMODYMonogenic diabetesPolygenic riskPrecision medicine

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Area of Science:

  • Genetics
  • Endocrinology
  • Metabolic Diseases

Background:

  • Glucokinase maturity-onset diabetes of the young (GCK-MODY) causes mild, lifelong hyperglycemia with high penetrance.
  • The variability in glycemic phenotype among GCK-MODY carriers is not fully explained.
  • Polygenic background is hypothesized to contribute to this variability and differ from HNF1A-MODY.

Purpose of the Study:

  • To investigate whether polygenic background influences the clinical phenotype of GCK-MODY.
  • To compare the polygenic contribution in GCK-MODY with HNF1A-MODY.
  • To assess the association between polygenic risk scores (PGS) and glycemic measures in GCK-MODY.

Main Methods:

  • Analyzed polygenic risk scores (PGS) for nine diabetes-related traits in 897 clinically referred GCK-MODY individuals.
  • Compared GCK-MODY individuals with non-diabetic controls, type 2 diabetes patients, and HNF1A-MODY patients.
  • Evaluated 158 clinically unselected GCK variant carriers from the UK Biobank to assess polygenic effects independently of clinical referral.

Main Results:

  • Clinically referred GCK-MODY individuals showed polygenic enrichment for HbA1c, fasting glucose, and type 2 diabetes compared to controls.
  • HbA1c and fasting glucose PGS were higher in GCK-MODY than in type 2 diabetes and HNF1A-MODY groups.
  • No polygenic enrichment was observed in clinically unselected GCK variant carriers, but HbA1c PGS associated with measured HbA1c levels.

Conclusions:

  • Polygenic background and GCK variants interact to modify the glycemic expression of GCK-MODY, impacting clinical diagnosis.
  • The pattern of polygenic contribution in GCK-MODY is distinct from HNF1A-MODY.
  • Understanding both monogenic and polygenic factors is crucial for explaining phenotypic variability in monogenic diseases.