Research Spotlight: Understanding Rare Genetic Variants That Cause Diabetes

Alicia-Huerta, Miriam Udler and Josep M Mercader, Investigators at the Diabetes Unit and Center for Genomic Medicine at Massachusetts General Hospital and at the Broad Institute of MIT and Harvard, and colleagues are lead and senior authors of a recently published paper in Nature Genetics, Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes

How would you summarize your study for a lay audience?

Diabetes is a disease caused by a combination of genetic and environmental factors.

Some types of diabetes are caused by genetic changes with a very strong effect in one gene, which are generally termed, monogenic diabetes. Patients with this type of diabetes typically have early onset and may benefit from specific diabetes drug or treatment strategy depending on the gene that is affected.

For patients suspected of having monogenic diabetes, identifying the mutation and the causal gene is very important but also very challenging, because it is hard to distinguish the variants that can cause the disease from those that have a benign effect.

In this study, we created a very large dataset of rare genetic variants and their association with diabetes, which can help us distinguish those variants more likely to cause monogenic diabetes vs those that are benign.

Using advanced analytical techniques that allow rare variant analysis, combining a technique called genotype imputation  with whole-genome sequencing, we were able to interrogate variants that are as rare as one in every 10,000 individuals in over 400,000 participants with and without diabetes from diverse ancestries from several cohorts and biobanks, including the Mass General Brigham Biobank.

We identified several rare variants associated with type 2 diabetes, including those present in genes known to cause monogenic diabetes and increasing the risk for diabetes up to eightfold. Carriers of these variants exhibited characteristics that were in between those with monogenic diabetes and those with common type 2 diabetes.

We define these types of variants as variants of intermediate penetrance, and we observe that their effect depends on the polygenic background of the individual.

In addition, we propose that our results can help interpret the variants that are identified when a patient with suspected monogenic diabetes is sequenced and distinguish those variants that are more likely to be benign from those that are more likely to be the pathogenic ones causing disease.

We hope that this will ultimately help diagnose patients with monogenic diabetes.

What are the implications and next steps?

The results from this study can help classify variants that are currently of uncertain significance (VUS) and provide support for classifying them as benign, pathogenic or of intermediate penetrance.

The next steps are to develop a framework for clinical reporting of these variants, understanding the clinical implications of these variants of intermediate penetrance, and how their identification can guide clinical care.