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Type 2 Diabetes GWAS in Japan Leads to Seven New Risk Loci

NEW YORK (GenomeWeb) – Seven new loci have been linked to type 2 diabetes in the Japanese population, according to a study published online this week in Nature Communications.

An international team led by investigators in Japan did a multi-stage genome-wide association study meta-analysis involving 23,399 individuals with T2D, and more than 31,700 unaffected controls. Along with known risk variants, the analysis detected SNPs at sites in the genome not linked to T2D in the past, including four loci that seemed to coincide with risk of the disease in several other populations.

Those involved in the study noted that the findings "indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities."

The researchers began by considering more than 7.5 million directly genotyped and imputed SNPs in a discovery group comprised of 9,817 T2D cases and 6,763 controls from Japan. Its second discovery set included another 5,646 Japanese individuals with T2D and 19,420 healthy individuals, profiled at the same autosomal SNPs.

In a meta-analysis of these cases and controls, the team narrowed in on 42 suspicious loci, including 25 sites that had previously been associated with T2D. To explore potential T2D ties at the 17 loci not previously implicated in the disease, it tested lead SNPs at each locus in 7,936 newly genotyped Japanese T2D cases and 5,539 controls.

That validation step, combined with a meta-analysis involving cases and controls from all three Japanese cohorts, left the researchers with seven loci falling in and around CCDC85A, FAM60A, DMRTA1, ASB3, ATP8B2, MIR4686, and INAFM2.

None one of the new T2D-associated variants showed ties to disease-related traits such as fasting glucose levels or insulin resistance in Japanese individuals from the validation group, the researchers reported.

Even so, they noted that the SNP at the DMRTA1 locus appeared to coincide with lower-than-usual fasting blood insulin levels in publicly available GWAS data for individuals of European ancestry, while the MIR4686 locus variant seemed to correspond with a jump in fasting plasma insulin in that dataset.

To look at whether the T2D associations held up in populations outside of Japan, the team tapped existing GWAS data for individuals with or without T2D of East Asian, South Asian, European, and Mexican or Latino ancestry.

Based on an analysis involving 8,200 to more than 160,800 individuals per population, it found that four of the SNPs — variants falling near FAM60A, DMRTA1, MIR4686, and INAFM2 — remained associated with T2D in the multi-ethnic analysis. The ATP8B2 locus showed more tenuous ties to T2D in the non-Japanese populations.

Through an analysis of new and known T2D-associated SNPs in obese and non-obese individuals from Japan, meanwhile, the researchers detected body mass index-related effect size differences for at least some previously detected risk SNPs.

Finally, the researchers looked for overlap between genes falling in and around known T2D-linked loci and those targeted by approved or experimental drug compounds, narrowing in on 83 shared genes — a set that included three genes targeted by existing T2D drugs and two more genes with noted biological roles in the disease.

The authors concluded that "systemic approaches for integrating the finding of genetic, biological, and pharmacological studies could be useful for developing new T2D treatments, although additional pipeline refinement would be required."