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Multi-Ancestry Type 2 Diabetes Genetic Study Discovers Hundreds of Novel Loci

NEW YORK – An international team of researchers has discovered hundreds of novel genetic loci linked to type 2 diabetes (T2D) risk in diverse populations.

In their genome-wide association study, published in Nature Genetics on Monday, the researchers found 318 novel autosomal and X-chromosomal variants associated with T2D and T2D-related vascular outcomes using data from almost 230,000 cases and 1.2 million controls with European, African American, Hispanic, South Asian, and East Asian ancestry.

The data for their meta-analysis came from a number of biobanks and consortia with non-overlapping participants, including the Million Veteran Program (MVP), which contributed over 40 percent of the T2D cases. Other contributors were the DIAMANTE Consortium, Penn Medicine Biobank, the Pakistan Genomic Resource, Biobank Japan, the Malmö Diet and Cancer Study, Medstar, and PennCath. The study included 56,000 African American participants, which is "substantially larger than previous African-specific studies published to date," according to the authors.

"While some is known about the genetic basis of type 2 diabetes, we reasoned that doubling the number of T2D cases would improve statistical power and lead to a host of new discoveries," said Benjamin Voight, a researcher at the University of Pennsylvania and the VA Medical Center in Philadelphia, and a co-corresponding author of the study, in an email.

One goal of the study was to help researchers more rapidly find ways to improve healthcare and treatment for the veteran population, said Voight. "The veteran population is also at heightened risk for cardiometabolic disease, so our group finds ourselves motivated to study, and understand as quickly as possible, the genetic underpinning of diseases like T2D," he said.

Overall, the team discovered 558 independent SNPs associated with T2D. An additional 21 SNPs were ancestry-specific to Europeans. Focusing on African American participants, the researchers found 21 loci associated with T2D susceptibility, three of which were novel and specific to this group. In the Hispanic subgroup, they identified two SNPs linked to T2D, which tagged previously reported loci. Among the Asian subgroup, they did not find any novel loci associated with T2D.  

Through transcriptome-wide association analyses, the team then identified 804 putative causal genes, including 54 genes that are possible targets for drugs and compounds approved by the US Food and Drug Administration.

The researchers also found that T2D patients with a high polygenic risk for T2D had a strongly increased risk for retinopathy, as well as an increased risk for chronic kidney disease (CKD), peripheral artery diseases (PAD), and neuropathy. This, they wrote, could help identify diabetes patients at risk of developing these conditions.

The plan moving forward involves many strategies, Voight said. The team wants to collect and analyze more genetic data, as well as additional diabetes-related traits from the MVP participants, such as obesity, fatty liver, and heart disease. Identifying specific proteins linked to heightened susceptibility is another step Voight wants to take, along with using computational, collaborative, or chemical screening efforts to discover compounds that could be possible leads for therapies. In addition, the group has a special interest in helping patients with susceptibility for diabetes who come from African American and Hispanic backgrounds.

"We are also particularly interested in utilizing all of the genetic markers genome-wide to predict diabetes risk, particularly in African American and Latinx subjects, patient populations with the gravest health disparities," Voight said.  

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