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

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.