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Type 2 Diabetes GWAS Meta-Analysis in Japanese Population Identifies 28 Novel Risk Loci

NEW YORK (GenomeWeb) – Researchers have uncovered more than two dozen new genetic loci that are linked to type 2 diabetes in the Japanese population.

More than 150 diabetes susceptibility loci have been reported so far, but most of these were uncovered in populations of European ancestry. As type 2 diabetes epidemiology differs between people of Japanese and European ancestry, researchers led by the University of Tokyo's Takashi Kadowaki conducted a meta-analysis of four genome-wide association studies examining type 2 diabetes risk among more than 36,600 cases and 155,100 controls, all of Japanese ancestry.

In their analysis, the researchers linked 88 loci to type 2 diabetes, about a third of which were novel. While many of the lead variants at these loci were common among both Japanese and European individuals, the researchers noted that some of the newly uncovered variants were more prevalent among Japanese individuals.

"Together, these findings provide insights into the etiology of type 2 diabetes in Japanese and Europeans," Kadowaki and his colleagues wrote in their paper, which was published today in Nature Genetics.

He and his colleagues conducted two new GWAS using cohorts of Japanese ancestry. In this, they relied on 1000 Genomes project phase 3 data as an imputation reference panel. At the same time, they re-analyzed two GWAS they previously performed with this updated reference panel. In the past, researchers reported uncovering seven novel type 2 diabetes loci in those cohorts.

When the researchers now combined those four GWAS into a meta-analysis, they uncovered genome-wide significant associations at 88 loci, 28 of which were novel.

Three-quarters of the lead variants at these loci were common among both Japanese individuals in these cohorts and European individuals from the 1000 Genomes phase 3 cohort. The effect sizes of these variants were also largely consistent and in the same direction, the researchers noted. Similarly, when they examined the effect size of lead variants from a European type 2 diabetes GWAS, they also found a strong positive correlation and directional consistency in the two populations.

This, the researchers noted, suggests most type 2 diabetes susceptibility loci —whether uncovered in a European or a Japanese population — would have similar effects on the other population.

After a stepwise analysis that uncovered 27 additional signals, the researchers traced these 115 signals to find 28 missense variants in 21 genes in linkage disequilibrium.

Some of these variants, though, were more common among Japanese individuals, including p.Ala341Thr in CPA1, p.Val282Met in GP2, and p.Arg131Gln in GLP1R. CPA1 and GP2, the researchers noted, have been linked to the differentiation of exocrine pancreatic acinar cells and are specifically expressed in the pancreas.

GLP1R, meanwhile, encodes a receptor for glucagon-like peptide 1, which induces glucose-dependent insulin secretion. GLP1R agonists, the researchers pointed out, are common type 2 diabetes drugs, and the p.Arg131Gln variant in GLP1R could be a potential marker for response to the drug among East Asians.

The researchers also compared whether the molecular pathways implicated by GWAS in Japanese or European individuals differed. Of the more than 1,000 pathways they examined, 17 were associated with type 2 diabetes in Japanese individuals and 13 with type 2 diabetes in Europeans. Pathways involving beta cell function, development, prostate cancer, and G1 stage were linked to type 2 diabetes in both populations. However, NOTCH signaling and insulin secretion pathways were more strongly associated with disease in one population than the other.

"Because the difference in the power of the GWAS may lead to different associations of pathways with type 2 diabetes in Japanese and European individuals, these pathways should be assessed in larger GWAS in the future," the researchers concluded.