Polygenic background contributes to GCK-MODY clinical presentation and glycaemic variability
Authors' conclusion
Our findings suggest that polygenic background and GCK variants interact to modify the glycaemic expression of GCK-MODY, influencing clinical diagnosis despite high penetrance. The pattern of polygenic contribution differs from that of HNF1A-MODY, highlighting the aetiology specific interaction.
Study context
- Population
- Clinically referred individuals with GCK-MODY and clinically unselected GCK variant carriers from the UK Biobank
- Participants
- 897 / 7,645 / 4,773 / 601 / 158
- Comparison
- PGS in GCK-MODY vs non-diabetic controls, T2D and HNF1A-MODY
- GCK-MODYn = 897
- Non-diabetic controlsn = 7,645reference
- T2Dn = 4,773
- HNF1A-MODYn = 601
- UK Biobank GCK carriersn = 158
- Outcome
- Polygenic risk scores for nine diabetes-related traits and their associations with glycaemic measures
Methodological detailscase-control comparison, population-based validation cohort (UK Biobank)
- Case-control comparison
- Population-based validation cohort (UK Biobank)
Performance
As reported in the abstract
Difference
0.16-0.33 SD
all p<0.003
GCK-MODY · HbA1c, fasting glucose and T2D PGS; not for T1D
Difference
0.33 SD
P < 1 × 10⁻27
HNF1A-MODY · T2D PGS only contributed independently
Further findings
| Outcome | GCK-MODY | UK Biobank GCK carriers |
|---|---|---|
| Association of HbA1c PGS with measured HbA1c in GCK carriers | ||
| β | 0.97 | 0.91 |
Association of HbA1c PGS with measured HbA1c in GCK carriers
- Both p<0.009; effect sizes similar to non-carriers
Risk of exceeding diabetes diagnostic HbA1c threshold (≥48 mmol/mol), top HbA1c PGS quintile
- 3-to-6-fold risk in clinically selected and clinically unselected cohort respectively
Original publication
Composed by AI from the published abstract and checked against it. How Briefs are made →