The contribution of polygenic background in young onset monogenic disorders needs further exploration. Understanding this will provide new biological insights and may improve risk prediction of monogenic disease. Here we investigated the role of polygenic background in MODY, a common monogenic disorder with an age-dependent onset. We found strong enrichment of type 2 diabetes (T2D) polygenic risk, but not type 1 diabetes risk, in genetically confirmed MODY cases. This T2D polygenic burden, primarily through beta-cell dysfunction pathways, was strongly associated with earlier age of diagnosis and increased diabetes severity. Common genetic variants collectively accounted for 24% (p<0.0001) of the phenotypic variability. Using a large population cohort, we demonstrated that T2D polygenic burden substantially modifies diabetes onset in individuals with pathogenic variants, with diabetes risk ranging from 11% to 81%. Finally, we show that individuals with MODY-like phenotypes without a causal variant had elevated polygenic burden for T2D and related traits representing potential polygenic phenocopies. These findings reveal substantial influence of common genetic variation in shaping the clinical presentation of early-onset monogenic disorders. Incorporating these may improve risk estimates for individuals carrying pathogenic monogenic variants.

The authors have declared no competing interest.

The research utilised data from the UK Biobank resource carried out under UK Biobank application number 103356. UK Biobank protocols were approved by the National Research Ethics Service Committee. KAP is funded by Wellcome Trust (219606/Z/19/Z), ATH is supported by Wellcome Trust Senior Investigator award (WT098395/Z/12/Z). 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.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the North Wales ethics committee (22/WA/0268). The UK Biobank Research Ethics Committee approved the study, and all participants provided written informed consent

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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 https://biobank.ctsu.ox.ac.uk