New research from a large international team of scientists offers a more complete picture of the genes responsible for type 2 diabetes, demonstrating that previously identified common alleles shared by many in the world are the biggest culprits—not the less common variants some scientists had hypothesized might play a large role in who gets the disease.

The researchers also identified a novel variant specific to East Asians through their study that analyzed the genes of individuals from five ethnic groups, making this the largest multi-ethnic genetic sequencing study published to date.

Their findings are reported in the July 11 issue of Nature.

Led by researchers at the University of Michigan School of Public Health, the Wellcome Trust Centre for Human Genetics at the University of Oxford, the Broad Institute of MIT and Harvard, and the Massachusetts General Hospital, more than 300 scientists from 22 countries used DNA from 120,000 individuals to pinpoint genes and their variants, which influence the disease that impacts 10 percent of the world’s population.

A variant TM6SF2 gene causes susceptibility to nonalcoholic fatty liver disease due to impaired very low density lipoprotein (VLDL) production14.[21]

TM6SF2 inhibition was associated with reduced secretion of TG-rich lipoproteins (TRLs) and increased cellular TG concentration and lipid droplet content, whereas TM6SF2 overexpression reduced liver cell steatosis. TM6SF2 is a regulator of liver fat metabolism with opposing effects on the secretion of TRLs and hepatic lipid droplet content.

“Our study has taken us to the most complete understanding yet of the genetic architecture of type 2 diabetes,” said Michael Boehnke, the Richard G. Cornell Distinguished University Professor of Biostatistics, director of the Center for Statistical Genetics at the U-M School of Public Health and one of three senior authors of the study. “With this in-depth analysis we have obtained a more complete picture of the number and characteristics of the genetic variants that influence type 2 diabetes risk.”

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”), influences risk of type 2 diabetes.

The researchers completed whole genome sequencing of more than 2,600 people and exome sequencing of 13,000, complemented with genome- or exome-wide array genotyping of 111,000 people. Exomes are the portion of the genome that code for proteins.

Type 2 diabetes is a major threat to global public health as deaths from the disease continue to rise rapidly, along with its complications including blindness, kidney failure, heart attack, stroke and amputation. Type 2 is the most common form of the diabetes; it impacts the body’s ability to regulate glucose (or sugar). In addition to its genetic components, environment and behavior play major roles in who gets the disease, with obesity, excessive stress and an inactive lifestyle among the contributors. Combined with other risk factors such as smoking, high cholesterol and high blood pressure, people with type 2 diabetes have a much higher risk of cardiovascular disease.

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