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Rare Type 2 Diabetes Risk Variants Identified in Exome Sequencing Study

NEW YORK (GenomeWeb) – Members of a large international team led by investigators at the Broad Institute, the University of Michigan, the University of Oxford, and elsewhere have identified previously unappreciated rare variants contributing to type 2 diabetes (T2D) that occur particularly in certain genes and pathways.

"Our results provide a nuanced description of rare variation and the association with T2D, which might also apply to other complex disease," the authors wrote in a study published in Nature today.

Through exome sequencing on almost 20,800 individuals with T2D and more than 24,400 T2D-free controls from five ancestral groups, the researchers focused in on 16 gene sets marked by rare variants with ties to T2D. In the process, they saw variants with exome-wide significant T2D associations in four genes, including dozens of variants in a gene called SLC30A8 that appear to impart protection from T2D.

From the findings so far, the team estimated that it would need to sequence on the order of 75,000 to 185,000 individuals with T2D to find exome-wide significant gene-level associations for additional rare variants flagged in the analysis. In the meantime, the group outlined a strategy for evaluating more modest associations involving rare variants to aid drug development or disease biology studies.

In a statement, co-lead author Jason Flannick, who is affiliated with Harvard Medical School, Boston Children's Hospital, and the Broad Institute, noted that the current study highlighted rare variants "in many genes" that "could be targeted by new medications or studied to understand the fundamental processes underlying disease."

Prior genome-wide association studies have uncovered common variants contributing to T2D in several populations. For example, recent GWAS or GWAS meta-analyses have led to common variants contributing to T2D risk in Japan and China. It has been trickier to track down significant T2D associations by exome sequencing, the team noted, perhaps due to the large sample sizes needed to narrow in on the rare variants that exome or genome sequencing approaches reveal.

The authors noted that "for biological discovery in many complex traits, such as T2D, exome sequencing and array-based GWAS seem complementary: locus discovery and fine mapping are achieved most efficiently using larger array-based GWAS, whereas rare coding variant allelic series — that could aid experimental gene characterization or provide confidence in disease-gene identification — are best discoverable through sequencing."

To dig deeper into the rare variant side of the equation, the researchers sequenced protein-coding portions of the genome to an average of 40-fold coverage in almost 25,000 T2D cases and as many unaffected controls, including individuals with self-reported Hispanic/Latino, European, African American, East Asian, or South Asian ancestry.

"Most large population studies focus on individuals of European ancestry, and that can make it hard to generalize the results globally," co-senior author Michael Boehnke, director of the University of Michigan School of Public Health Center for Statistical Genetics, said in a statement. "The more diverse the cohort makes for better, more informative science."

After tossing out variants and samples that were duplicated or did not meet quality control criteria, the team was left with information about more than 6.3 million variants in 20,791 individuals with T2D and 24,440 without.

The researchers' initial analyses highlighted 15 variants at seven loci that reached exome-wide significance in the T2D cases, while their gene-focused analyses led to significant T2D associations in the MC4R, SLC30A8, and PAM genes. They verified the gene-level links in two more exome-sequenced cohorts with European or African American ancestry and went on to track down another, more nominal, T2D association involving the PDX1 gene.

When the team pulled back further to consider genes containing variants with more modest T2D links, meanwhile, it identified 16 suspicious gene sets that were interrogated further in subsequent gene prioritization analyses. The suite of rare variants with potential roles in T2D was also set alongside loci found by GWAS done with array-based genotypes from more than 34,500 of the exome-sequenced cases or controls.

The investigators are making findings from the T2D exome study available to other researchers through an online "Type 2 Diabetes Knowledge Portal," established through an Accelerating Medicines Partnership between the National Institutes of Health, the US Food and Drug Administration, several nonprofits, and 10 biopharma companies.