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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\n                      <jats:italic>HNF1A<\/jats:italic>\n                      -MODY.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To test whether polygenic background contributes to the\n                      <jats:italic>GCK<\/jats:italic>\n                      -MODY clinical phenotype, we analysed polygenic risk scores (PGS) for nine diabetes-related traits in 897 clinically referred individuals with\n                      <jats:italic>GCK<\/jats:italic>\n                      -MODY. We compared these to 7645 non-diabetic control participants, 4773 participants with type 2 diabetes and 601 participants with\n                      <jats:italic>HNF1A<\/jats:italic>\n                      -MODY and assessed associations between PGS and glycaemic measures. Additionally, we evaluated 158 clinically unselected\n                      <jats:italic>GCK<\/jats:italic>\n                      variant carriers from the UK Biobank to examine polygenic effects independent of clinical referral.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We observed independent polygenic enrichment for HbA\n                      <jats:sub>1c<\/jats:sub>\n                      (including both glycaemic and non-glycaemic components), fasting glucose and type 2 diabetes in clinically referred\n                      <jats:italic>GCK<\/jats:italic>\n                      -MODY individuals compared with non-diabetes controls (0.16\u20130.33 SD higher, all\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.003), but not for type 1 diabetes. Importantly, HbA\n                      <jats:sub>1c<\/jats:sub>\n                      and fasting glucose PGSs were higher than in both type 2 diabetes and\n                      <jats:italic>HNF1A<\/jats:italic>\n                      -MODY groups, whereas type 2 diabetes PGS was lower.\n                      <jats:italic>GCK<\/jats:italic>\n                      -MODY and\n                      <jats:italic>HNF1A<\/jats:italic>\n                      -MODY showed distinct patterns of polygenic enrichment, with only the type 2 diabetes PGS contributing independently in\n                      <jats:italic>HNF1A<\/jats:italic>\n                      -MODY (0.33 SD,\n                      <jats:italic>p<\/jats:italic>\n                      &lt;1\u00a0\u00d7\u00a010\u207b\n                      <jats:sup>27<\/jats:sup>\n                      ). By contrast, no polygenic enrichment was seen in\n                      <jats:italic>GCK<\/jats:italic>\n                      pathogenic variant carriers from a clinically unselected population-based cohort. In both settings, HbA\n                      <jats:sub>1c<\/jats:sub>\n                      PGS were associated with measured HbA\n                      <jats:sub>1c<\/jats:sub>\n                      levels in\n                      <jats:italic>GCK<\/jats:italic>\n                      carriers (clinically referred: \u03b2=0.97, clinically unselected: \u03b2=0.91, both\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.009), with effect sizes similar to those in non-carriers.\n                      <jats:italic>GCK<\/jats:italic>\n                      -MODY cases in the top HbA\n                      <jats:sub>1c<\/jats:sub>\n                      quintile had a 3-to-6-fold risk of exceeding the diabetes diagnostic HbA\n                      <jats:sub>1c<\/jats:sub>\n                      threshold (\u226548 mmol\/mol) in clinically selected and clinically unselected cohort respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      Our findings suggest that polygenic background and\n                      <jats:italic>GCK<\/jats:italic>\n                      variants interact to modify the glycaemic expression of\n                      <jats:italic>GCK<\/jats:italic>\n                      -MODY, influencing clinical diagnosis despite high penetrance. The pattern of polygenic contribution differs from that of\n                      <jats:italic>HNF1A<\/jats:italic>\n                      -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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06712-7","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T12:14:36Z","timestamp":1773836076000},"page":"1951-1961","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Polygenic background contributes to GCK-MODY clinical presentation and glycaemic variability"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6990-5826","authenticated-orcid":false,"given":"Jacques","family":"Murray Leech","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0365-9235","authenticated-orcid":false,"given":"Ankit M.","family":"Arni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6348-5565","authenticated-orcid":false,"given":"V. 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UK Biobank protocols were approved by the National Research Ethics Service Committee. The work is supported by the National Institute for Health Research (NIHR) Exeter Biomedical Research Centre, Exeter, UK. The Wellcome Trust, MRC and NIHR had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed are those of the author(s) and not necessarily those of the Wellcome Trust, Department of Health, NHS or NIHR. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data supporting the findings of this study are available within the article and its supplemental information. The clinical data generated and\/or analysed as part of this study are not publicly available because of patient confidentiality and ethical approval associated with the data but are available from the corresponding authors upon reasonable request. The UK Biobank dataset is available from:","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The current work is funded by Diabetes UK (19\/0005994 and 21\/0006335) and MRC (MR\/T00200X\/1). KAP is funded by the Wellcome Trust (219606\/Z\/19\/Z). ATH is supported by Wellcome Trust Senior Investigator award (WT098395\/Z\/12\/Z).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"KAP, MNW, ATH and KC contributed to the study concept, design and data acquisition. JML, AMA, VKC, LNS and KAP were responsible for data curation and analysis. All authors contributed to manuscript revisions and approved the final version. KAP is the guarantor of the work and had full access to all study data, taking responsibility for the integrity of the data and the accuracy of the analyses.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}