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GWAS Uncovers Six New Type 2 Diabetes Risk Loci in South Asians

NEW YORK (GenomeWeb News) – A large international consortium reported online in Nature Genetics yesterday that it has identified a half-dozen risk loci for type 2 diabetes in the South Asian population that had previously not been found.

The team did a genome-wide association study involving thousands of people of South Asian ancestry — a population that's been estimated to be at as much as four times the diabetes risk seen in Europeans — with or without type 2 diabetes. The search uncovered both new and known type 2 diabetes-associated loci, along with variants associated with related processes such as insulin sensitivity and the function of insulin-producing beta cells in the pancreas.

"Our findings provide additional insights into mechanisms underlying [type 2 diabetes] and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to [type 2 diabetes]," senior author John Chambers, a cardiovascular epidemiology researcher at Imperial College London, and co-authors wrote.

Though environmental factors, such as diet and exercise play a part in type 2 diabetes risk, the study author explained, the disease is also highly heritable. Its increased prevalence in South Asian countries, such as India, Pakistan, Sri Lanka, and Bangladesh, suggests individuals in these populations might carry genetic risk factors not identified through past GWAS of individuals of European descent, they added. Studies in that population have uncovered type 2 diabetes-associated SNPs near dozens of genes.

"Although lifestyle factors such as unhealthy diet, physical inactivity and obesity are important causes of diabetes in South Asians, these are only part of the explanation," Chambers said in a statement. "Genetic factors have been widely considered to play a role in the increased risk of type 2 diabetes in Asians, but to date have not been systematically explored in this population."

For the discovery stage of the study, Chambers and his colleagues used Illumina 610, 660, or 317 arrays to genotype 5,561 individuals of South Asian descent with type 2 diabetes and 14,458 without. The study participants were from London, Pakistan, and Singapore and had been enrolled through the London Life Sciences Population study, the Pakistan Risk of Myocardial Infarction Study, and the Singapore Indian Eye study.

Because a dense haplotype map specific to the South Asian population was not available, the team noted, their GWAS relied solely on the nearly 569,000 SNPs that they could genotype directly and which met their quality control criteria.

For their subsequent analyses, the researchers looked at SNPs and loci that appeared to coincide with diabetes in South Asian men, women, and the population as a whole. They also used data on 8,130 cases and almost 39,000 controls of European ancestry to help identify loci that might contribute to risk in both the South Asian and European populations.

Through replication testing in 13,170 South Asian type 2 diabetes cases and 25,398 South Asian controls, along with meta-analysis testing of the cohorts overall, the team narrowed in on six SNPs that reached genome-wide significance and were located in and around the GRB14, ST6GAL1, VPS26A, AP3S2, HMG20A, and HNF4A genes. A dozen more SNPs showed modest associations with type 2 diabetes in the South Asian population.

Variants at two of these loci — in the ST6GAL1 and HNF4A genes — were also associated with the function of pancreatic beta cells, the team reported, while SNPs near the GRB14 gene appear to coincide with insulin sensitivity.

By sequencing about one million bases on each side of the six new risk loci in samples from 109 South Asians with the Illumina GAII, the researchers found 49,145 SNPs in these regions, including 24,902 SNPs that may be South Asian specific and are not found in 1000 Genomes Project or HapMap data.

When they looked at 42 loci with reported ties to type 2 diabetes from prior studies, the team found that 27 of these were associated with type 2 diabetes in South Asians. Meanwhile, additional follow-up studies hint that the newly detected risk variants also contribute to inherited risk of diabetes in European populations.

"We have shown that the genetic variants discovered here in South Asians also exist and contribute to diabetes in Europeans," lead author Jaspal Kooner, a researcher with Imperial College London's National Heart and Lung Institute, said in a statement. "Our studies in Asians and European populations highlight the importance and gain in examining the same problem in different ethnic groups."

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