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New Type 2 Diabetes Locus Identified in GWAS of African Populations

NEW YORK – A team led by investigators at the National Institutes of Health has uncovered new genetic contributors to type 2 diabetes (T2D) by studying populations in sub-Saharan Africa.

"The findings of this study further demonstrate why it is important to study all human populations. By doing so, we have the opportunity to make novel discoveries that will not only help the specific population but also people all around the globe," senior and corresponding author Charles Rotimi, director of the National Human Genome Research Institute (NHGRI) Center for Research on Genomics and Global Health, said in a statement.

As they reported online today in Nature Communications, Rotimi and his colleagues started with a genome-wide association study that included more than 5,200 individuals from Nigeria, Ghana, and Kenya with or without T2D. There, they identified 32 loci linked to T2D in prior studies, which were mainly conducted in individuals of European descent, as well as a new association involving a locus near ZRANB3.

As part of the Africa America Diabetes Mellitus (AADM) study, the researchers genotyped some 18 million autosomal SNPs in 2,343 participants from Nigeria, Ghana, or Kenya with T2D and 2,889 unaffected controls from the same populations who had similar average body mass indexes.

Along with known T2D risk loci, the analyses highlighted two ZRANB3 SNPs, which were missing from the 1000 Genomes Project database and the Genome Aggregation Database (GnomAD) and are suspected of being specific to some African populations. In a validation analysis that included T2D cases and controls from a Zulu population in South Africa, which had lower population frequencies of both SNPs compared to the AADM cohort, the team saw consistent directional effects, though the ties to T2D appeared to be less pronounced.

"In the early days of large-scale genomic studies, we did not know the effect of genes we found through our statistical tests," co-first author Adebowale Adeyemo, deputy director of the NHGRI's Center for Research on Genomics and Global Health, said in a statement. "But with the availability of new genomic tools, our next step was to ask: 'What does ZRANB3 do? How does it confer risk for T2D, and by what mechanisms does it act?' That is the knowledge that will help the results become actionable for patients."

For those functional experiments, the team used RNA sequencing, CRISPR-Cas9-based gene knockouts, and other approaches for fiddling with the expression of ZRANB3 in a zebrafish pancreas model of T2D. Results from such experiments indicated that the number of insulin-producing beta cells in the pancreas decrease as ZRANB3 activity is dialed down — results confirmed with small interfering RNA-based gene knockdown experiments in mice.

When they looked for T2D associations with more than 100 SNPs implicated in the condition in the past, meanwhile, the researchers verified 32 of these risk loci in the Nigerian, Ghanaian, or Kenyan cases. A handful more risk loci came out of their GWAS meta-analysis, which included data for almost 8,600 participants from African, African American, and other populations.

"Africa is the original cradle of all humanity, to which all humans can trace their genetic origin," said co-author Francis Collins, director of the NIH and a senior investigator with NHGRI's medical genomics and metabolic genetics branch, in a statement, noting that "studying the genomes of Africans offers important opportunities to understand genetic variation across all human populations."