ArticleNature metabolism2025
Common genetic variants modify disease risk and clinical presentation in monogenic diabetes.
Article in Nature metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- The central role of the β-cell in diabetes: from monogenic forms to type 1, type 2, and gestational diabetes.Reviews in endocrine & metabolic disorders · 2026Review
- Within-sibling attenuation of polygenic risk score accuracy: investigating the effects of principal component analysis, LD score regression, and mixed model association in the UK Biobank.Human genetics · 2026Article
- Polygenic scores as modifiers in Mendelian diseases.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2026Article
- Polygenic background contributes to GCK-MODY clinical presentation and glycaemic variability.Diabetologia · 2026Article
- Evaluation of rare NR1D2 variants in MODY-X: clinical, genetic, and in silico insights.Journal of endocrinological investigation · 2026Article
- Combinatorial effects of gene dosage, polygenic background and environment on complex traits.medRxiv : the preprint server for health sciences · 2026Article
- Insight from polygenic modifiers in Asian monogenic diabetes.Journal of diabetes investigation · 2026Article
- High prevalence of maturity-onset diabetes of the young in the Czech Republic: A 25-year nationwide registry-based study.Diabetic medicine : a journal of the British Diabetic Association · 2026Article
- Evaluation of the genome-informed risk assessment (GIRA) approach from eMERGE in an independent health system.medRxiv : the preprint server for health sciences · 2026Article
- The conundrum in diagnosing Maturity-Onset Diabetes of the Young (MODY) in a large German pedigree with early-onset diabetes and a novel HNF1A variant.Molecular and cellular pediatrics · 2026Article
- Phenotypic heterogeneity and polygenic risk scores in a family of maturity-onset diabetes of the young.JCEM case reports · 2026Article
- Maturity Onset Diabetes of the Young (MODY): French National Diagnosis and Care Protocol (PNDS, Protocole National de Diagnostic et de Soins).Orphanet journal of rare diseases · 2026Review
- The Genetic Landscape of Diabetes Mellitus: Lessons from Monogenic and Polygenic Forms.Life (Basel, Switzerland) · 2026Review
- A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data.EMBO molecular medicine · 2026Article
- Clinical implications of rare and common variation in preimplantation genetic testing for breast cancer.NPJ genomic medicine · 2026Article
- Genomic landscape of Mexican patients with maturity onset diabetes of the young: beyond mutations in MODY-known genes.Frontiers in endocrinology · 2026Article
- Identification of maturity-onset diabetes of the young through targeted next-generation sequencing in Thai patients with atypical diabetes in real-world practice.Frontiers in endocrinology · 2026Article
- Clinical and functional characteristics of theFrontiers in endocrinology · 2026Article
- Global perspectives on monogenic forms of diabetes.Diabetologia · 2025Review
- Clinical implications of rare and common variation in preimplantation genetic testing for breast cancer.medRxiv : the preprint server for health sciences · 2025Article
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9 authors.
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Abstract
Young-onset monogenic disorders often show variable penetrance, yet the underlying causes remain poorly understood. Uncovering these influences could reveal new biological mechanisms and enhance risk prediction for monogenic diseases. Here we show that polygenic background substantially shapes the clinical presentation of maturity-onset diabetes of the young (MODY), a common monogenic form of diabetes that typically presents in adolescence or early adulthood. We find strong enrichment of type 2 diabetes (T2D) polygenic risk, but not type 1 diabetes risk, in genetically confirmed MODY cases (n = 1,462). This T2D polygenic burden, primarily through beta-cell dysfunction pathways, is strongly associated with earlier age of diagnosis and increased diabetes severity. Common genetic variants collectively account for 24% (P < 0.0001) of the phenotypic variability. Using a large population cohort (n = 424,553), we demonstrate 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 (n = 300) without a causal variant have 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 variants.
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