ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and beta-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in 2 subjects and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY and Type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank. We identified a biallelic frameshift ONECUT1 variant as the cause of NDM in one individual. However, we found no enrichment of missense or null ONECUT1 variants among 484 individuals clinically suspected of MODY, in whom all known genes had been excluded. Finally, using a rare variant burden test in the UK Biobank European cohort, we identified a significant association between heterozygous ONECUT1 null variants and type 2 diabetes (P=0.006) but did not find association between missense variants and type 2 diabetes. Our results confirm biallelic ONECUT1 variants as a cause of NDM and highlight monoallelic null variants as a risk factor for type 2 diabetes. These findings confirm the critical role of ONECUT1 in human beta-cell function.
This work is funded by Diabetes UK (19/0005994 and 21/0006335), MRC (MR/T00200X/1), Wellcome Trust (224600/Z/21/Z) and Wellcome Trust’s Institutional Strategic Support Fund awarded to University of Exeter. E.D.F. is a Diabetes UK RD Lawrence Fellow (19/005971). K.A.P. is funded by the Wellcome Trust (219606/Z/19/Z). A.T.H. is employed as a core member of staff within the National Institute for Health Research–funded Exeter Clinical Research Facility and is an NIHR Emeritus Senior Investigator. S.E.F. has a Wellcome Trust Senior Research Fellowship (223187/Z/21/Z). T.W.L. has a lectureship funded by a Research England’s Expanding Excellence in England (E3) award. M.B.J. and M.N.We. are recipients of an Exeter Diabetes Centre of Excellence Independent Fellowship funded by Research England’s Expanding Excellence in England (E3) fund. M.B.J. and has been the recipient of an EASD Rising Star fellowship during this study. 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.