Evidence map›Paper›PMID 41848901›Full record

ArticleDiabetologia2026

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

Jacques Murray Leech, Ankit M Arni, V Kartik Chundru, Luke N Sharp, Kevin Colclough, Andrew T Hattersley, Michael N Weedon, Kashyap A Patel

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In one paragraph

Article in Diabetologia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Jacques Murray LeechDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.ORCID http://orcid.org/0000-0001-6990-5826
Ankit M ArniDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.ORCID http://orcid.org/0009-0005-0365-9235
V Kartik ChundruDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.ORCID http://orcid.org/0000-0002-6348-5565
Luke N SharpDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.ORCID http://orcid.org/0009-0001-3657-5493
Kevin ColcloughExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.ORCID http://orcid.org/0000-0003-0566-4853
Andrew T HattersleyDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.ORCID http://orcid.org/0000-0001-5620-473X
Michael N WeedonDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.ORCID http://orcid.org/0000-0002-6174-6135
Kashyap A PatelDepartment of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK. K.A.Patel@exeter.ac.uk.ORCID http://orcid.org/0000-0002-9240-8104

Funding

Diabetes UK 19/0005994Diabetes UK 21/0006335Medical Research Council MR/T00200X/1Wellcome Trust 219606/Z/19/ZWellcome Trust WT098395/Z/12/Z
6 · The paper itself

Abstract

aims/hypothesisGCK-MODY (glucokinase MODY) causes lifelong, mild hyperglycaemia with high penetrance. Variation in glycaemic phenotype among carriers remains unexplained. We hypothesised that polygenic background contributes to this variability and that this influence differs from that of HNF1A-MODY.

methodsTo test whether polygenic background contributes to the GCK-MODY clinical phenotype, we analysed polygenic risk scores (PGS) for nine diabetes-related traits in 897 clinically referred individuals with GCK-MODY. We compared these to 7645 non-diabetic control participants, 4773 participants with type 2 diabetes and 601 participants with HNF1A-MODY and assessed associations between PGS and glycaemic measures. Additionally, we evaluated 158 clinically unselected GCK variant carriers from the UK Biobank to examine polygenic effects independent of clinical referral.

resultsWe observed independent polygenic enrichment for HbA CONCLUSIONS/

interpretationOur 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. Our study highlights the importance of integrating both monogenic and polygenic factors to better understand phenotypic variability in monogenic diseases.

Indexed as

Blood GlucoseDiabetes Mellitus, Type 2GlucokinaseMultifactorial InheritanceAdultFemaleGenetic Predisposition to DiseaseGenetic Risk ScoreGlycated HemoglobinHepatocyte Nuclear Factor 1-alphaHumansMaleMiddle AgedPhenotypeBlood GlucoseGlucokinaseGlycated Hemoglobinhemoglobin A1c protein, humanHepatocyte Nuclear Factor 1-alphaHNF1A protein, humanDiabetesGenetic riskGeneticsGlucokinaseHbA1cMODYMonogenic diabetesPolygenic riskPrecision medicine

Identifiers

PMID41848901
PMCPMC13236825

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.