The common disease of type 2 diabetes mellitus (T2DM) is genetically distinct from, but clinically similar to, rarer forms of diabetes mellitus
Today, understanding of the pathophysiology of rare forms of diabetes mellitus is greater than that of the common form of T2DM
As genetic studies examine rarer variants in large populations, higher penetrance variants have been found for T2DM even as previously 'Mendelian' variants have been found to have lower penetrances
The increasing overlap between regions associated with T2DM and genes or variants relevant to monogenic diseases suggests an overlapping disease aetiology, possibly including distinct T2DM subtypes
We propose that a unified diabetes mellitus risk model, spanning variants of all frequencies and penetrances, might provide future insights into understanding or treatment of all forms of diabetes mellitus
Insights into the genetic basis of type 2 diabetes mellitus (T2DM) have been difficult to discern, despite substantial research. More is known about rare forms of diabetes mellitus, several of which share clinical and genetic features with the common form of T2DM. In this Review, we discuss the extent to which the study of rare and low-frequency mutations in large populations has begun to bridge the gap between rare and common forms of diabetes mellitus. We hypothesize that the perceived division between these diseases might be due, in part, to the historical ascertainment bias of genetic studies, rather than a clear distinction between disease pathophysiologies. We also discuss possible implications of a new model for the genetic basis of diabetes mellitus subtypes, where the boundary between subtypes becomes blurred.
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Stefan Johansson has received a grant from the Novo Nordisk Foundation (#15OC0016108). Pål R. Njølstad has received grants from the European Research Council (AdG; #293574), the Research Council of Norway (#240413), the KG Jebsen Foundation (Translational Research Center), the University of Bergen (Diabetes Group), and the Helse Vest (Strategic Fund).
The authors declare no competing financial interests.
A class of antidiabetic medication that increases insulin secretion by blockage of the ATP-sensitive potassium channel in the pancreas.
A trait whose inheritance pattern obeys the laws proposed by Gregor Mendel; characteristic of a disease caused by mutations in a single gene.
An approach for identifying disease genes by testing for co-segregation between DNA segments and phenotype in a familial study design.
- Next-generation sequencing
(NGS). A family of technologies for relatively inexpensive and high-throughput sequencing of DNA.
- Genome-wide association studies
(GWAS). An approach for identifying disease genes by testing many common genetic variants in different individuals for associations with a trait.
- Expression quantitative trait loci
(eQTL). A genomic region that is associated with variation in expression levels of mRNA.
- Allelic series
A number of alleles of a gene or chromosome region with a range of phenotypic and/or molecular effects; useful to infer a genetic–phenotypic 'dose-response' curve.
In a familial study, the first affected family member who seeks attention for a disease presentation.
A technique for precise and efficient editing of genetic information within a cell.
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Flannick, J., Johansson, S. & Njølstad, P. Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Nat Rev Endocrinol 12, 394–406 (2016). https://doi.org/10.1038/nrendo.2016.50
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