Risk of diabetes is due to common, rather than rare, genetic variants

John Murphy, MDLinx | July 13, 2016

The genetic risk of type 2 diabetes can be attributed mostly to common alleles that are widely shared among human populations and not due to rare alleles or those unique to individuals or families, according to a mammoth genetics study—the largest of its kind—that involved 300 scientists in 22 countries using DNA data from 120,000 people.


Genetic study of type 2 diabetes at Radcliffe Department of Medicine of University of Oxford

Video Summary

“In this study, we have been able to highlight, with unprecedented precision, a number of genes directly involved in the development of type 2 diabetes,” co-author Mark McCarthy, MD, explains in this University of Oxford video.

“Our study tells us that genetic risk for type 2 diabetes reflects hundreds or even thousands of different genetic variants, most of them shared across populations,” said co-lead author Jason Flannick, PhD, Senior Group Leader at the Broad Institute of Harvard and MIT, and Research Associate at Massachusetts General Hospital, in Boston, MA.

Dr. Flannick, along with two other co-lead authors and their 300-plus colleagues, published these results online July 11, 2016 in the journal Nature.

Prior to this study, scientists have had a longstanding debate (going back more than a century) about this issue. One side argued that genetic differences that influence predisposition to type 2 diabetes are caused by rare or unique faulty genes specific to an individual or a family. The other side held that that the genetic contribution to diabetes risk is predominantly located at common, widely shared sites.

This major study confirmed the latter argument, and it corroborated previous genome-wide association studies (GWAS) that identified more than 80 loci of predominantly common variants associated with type 2 diabetes.

These results are of more than academic interest, the authors noted, because genetic architecture plays a major role in the application of genetic diagnosis and precision medicine. Notably, this finding means that future efforts to develop a personalized approach to treatment will have to be customized to an individual's broader genetic profile.

“This large range of genetic effects may challenge efforts to deliver personalized, or precision, medicine,” Dr. Flannick said.

For this study, the researchers performed whole-genome sequencing in some individuals and exome sequencing in the rest. Subjects had ancestral origins in Europe, South Asia, East Asia, North and South America, and Africa. The population included both those with diabetes and those without it.

After sequencing, results showed that variants associated with type 2 diabetes were overwhelmingly common and most fell within regions identified by previous studies. However, the analysis also revealed a number of rare coding variants in about 30 genes already associated with rare familial forms of type 2 diabetes.

“Rare genetic changes still reveal huge clues to the processes that lead to diabetes,” wrote co-lead author Mark McCarthy, MD, Robert Turner Professor of Diabetic Medicine at the Wellcome Trust Centre for Human Genetics at the University of Oxford, in Oxford, UK, on his lab’s blog.

The analysis also found more than a dozen genes with type 2 diabetes risk variants that alter amino acid sequence. One such variant—in the TM6SF2 gene—is already known to be involved in the development of hepatic steatosis (fatty liver disease); this study showed that it also influences type 2 diabetes risk.

“These findings matter because they provide many important new insights into the biology of diabetes: some of the genes and pathways implicated may represent novel avenues for drug development,” Dr. McCarthy wrote.

Even though this is the largest such study to date, the researchers called for genome sequencing in an even greater number of individuals to connect the results to human population variation, physiology, and disease.

“To ensure that these challenges can be taken up by the wider research community, we have made the data from our study publicly accessible for researchers around the world in the hope that this will accelerate efforts to understand, prevent, and treat this condition,” Dr. Flannick said.

The data from this and other studies are now available through the T2D Knowledge Portal, developed as part of the Accelerating Medicines Partnership.

Dr. McCarthy summarized the study and its findings in this video by University of Oxford.