Researchers Discover Genetic Variants Linked to Type 2 Diabetes

In the largest study of its kind, researchers discovered hundreds of novel genetic variants linked to type 2 diabetes, potentially improving care for millions living with this disease.

A team from the Perelman School of Medicine at the University of Pennsylvania and the Veterans Health Administration’s (VHA) Corporal Michael J. Crescenz Veterans Affairs Medical Center (CMCVAMC) examined the genes of more than 200,000 people around the world with type 2 diabetes.

In addition to uncovering new genetic variants linked to the condition, researchers identified gene variants that vary by ethnicity, as well as variants tied to conditions related to type 2 diabetes like coronary heart disease and chronic kidney disease.

The group used data from the world’s largest biobank, the Million Veteran Program (MVP) in the VHA, as well as data from the DIAGRAM Consortium, the UK Biobank, the Penn Medicine Biobank, and Biobank Japan. Researchers analyzed a study population of 1.4 million people around the world, of whom almost 230,000 had type 2 diabetes.

The team then broke down the genetic makeup of those hundreds of thousands with type 2 diabetes and found 558 independent genetic variants that are differentially distributed between people with and without type 2 diabetes. Twenty-one of these variants were specific to European ancestry while seven were specific to African American ancestry. Of the 558 variants found, 286 had never been discovered.

Researchers set out to discover if certain genetic variants among this group of people could be linked to specific type 2 diabetes-related conditions.

“Ultimately, three were linked to coronary heart disease, two to acute ischemic stroke, four to retinopathy, two to chronic kidney disease, and one to neuropathy,” said Marijana Vujkovic, PhD, a biostatistician at both the Perelman School of Medicine at the University of Pennsylvania, VHA’s CMCVAMC and a co-leader for the VHA’s national MVP Cardiometabolic Working Group.

“Building on this research, the scientific community can assess which of the surrounding genes nearby the identified genetic variants is likely to be the causal gene that alters the risk of type-2 diabetes, and that could lead to early interventions to limit controllable risks of developing the condition.”

While the researchers found many genetic variants in people with type 2 diabetes, no one variant was labeled as the worst or most dangerous.

“However, just like heart disease, schizophrenia, or obesity, it is the accumulation of a large number of these variants that can add up to a considerable increase in risk,” said co-senior author Benjamin F. Voight, PhD, an associate professor of Systems Pharmacology and Translational Therapeutics at Penn, and a co-leader for the VHA’s national MVP Cardiometabolic Working Group.

“We hope this study can not only help find that subset of patients with substantial risk, but also to motivate new, future studies for treatments based on these findings.”

Knowing more about the genetic variants linked to type 2 diabetes could help identify potential therapeutic targets for type 2 diabetes. Researchers also noted that this information could help guide treatment plans for people with the disease who may be susceptible to specific diabetes complications.

Going forward, the researchers plan to conduct a long-term examination of how genetics influence disease progression among patients with type 2 diabetes and associated metabolic disorders. The group is also leveraging the list of newly-discovered genes to investigate medication interactions.

“Knowing the genetic susceptibility for diabetes complications in a patient already diagnosed with type-2 diabetes, for example through a cumulative genetic risk score, could help guide that patient’s care,” said co-senior-author Kyong-Mi Chang, MD, a professor of Medicine at Penn, Associate Chief of Staff for Research at VHA’s CMCVAMC and the Co-PI for the VHA’s MVP Merit Award that supported this work.

“As clinicians, we hope that these findings can ultimately be applied to improve the health outcomes for our patients including veterans.”