An international team of scientists has completed the most comprehensive genetic investigation to date of type 2 diabetes. The investigation reveals that rare genetic variants unique to individuals are less important than common, shared genetic variants. Although the investigation notes that most of the common variants were identified in previous studies, it also emphasizes that over a dozen genes merit closer scrutiny because they have been found to alter the structure or composition of the proteins they encode.

The current study’s primary finding—the realization that common variants are bigger culprits than rare variants—suggests that any personalized approach to the treatment and prevention of type 2 diabetes will need to be tailored on the basis of an individual’s broader genetic profile, as well as environmental factors. The additional finding—the identification of protein-altering genes—provides important clues to the potentially “druggable” disease mechanisms.

The study, which was led by the University of Oxford, the Broad Institute, and the University of Michigan, appeared July 12 in the journal Nature, in an article entitled, “The Genetic Architecture of Type 2 Diabetes.” The article described a DNA-sequencing project that encompassed samples from 120,000 people with ancestral origins in Europe, South and East Asia, the Americas, and Africa. The article also detailed how exome and whole-genome sequencing results were used to test the hypothesis that lower-frequency variants could explain much of the hereditability of type 2 diabetes left uncertain by previous studies.

“Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies,” the study’s authors indicated. “Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.”

Through the collaboration that combined two research projects—GoT2D and T2D-GENES—researchers identified more than a dozen genetic regions that harbor variants that influence risk to type 2 diabetes. The majority of these were common variants, found in all human populations, and most had previously been detected by other genome-wide association studies.

The team identified a novel association between type 2 diabetes and a variant in the gene PAX4, present only in individuals from East Asia, including Korea, China, and Singapore. They also demonstrated that variants in the gene TM6SF2, previously linked to hepatic steatosis (commonly known as “fatty liver”), influence risk of type 2 diabetes.

“This study highlights both the challenges we face, and the opportunities that exist, in resolving the complex processes underlying a disease such as type 2 diabetes,” said Mark McCarthy, a researcher at the Wellcome Trust Centre for Human Genetics at the University of Oxford, one of three senior authors on the paper. “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. These represent promising avenues for efforts to design new ways to treat or prevent the disease.”

“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,” added Jason Flannick, co-lead author and senior group leader at the Broad Institute of Harvard and MIT and research associate at the Massachusetts General Hospital. “This large range of genetic effects may challenge efforts to deliver personalized (or precision) medicine. However, 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.”

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