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Large Type 2 Diabetes Study Suggests Relatively Little Risk Due to Rare Variants

NEW YORK (GenomeWeb) – Rare, low-frequency genetic variants appear to contribute relatively little to type 2 diabetes (T2D) risk, according to a study published online today in Nature by members of the Genetics of Type 2 Diabetes (GoT2D) and Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-ethnic samples (T2D-GENES) consortia.

Led by investigators in the UK and the US, the researchers sequenced the genomes of nearly 2,700 individuals of European ancestry, comparing genetic patterns in those with or without T2D. They also scrutinized protein-coding portions of the genome in more than 12,900 T2D cases and controls from five ancestry groups and used imputation-assisted genotyping to assess variants in the genomes of nearly 111,550 other individuals.

The search spanned common and rare variants, highlighting potential functional alleles and uncovering some loci that appeared to confer population-specific risk for T2D. But most of the T2D-associated variants identified fell in and around sites implicated through prior genome-wide association studies that focused on common variants.

"Our study tells us that genetic risk for type 2 diabetes reflects hundreds or even thousands of different genetic variants, most of them shared across populations," co-first author Jason Flannick, a medical and population genetics researcher affiliated with the Broad Institute and Massachusetts General Hospital, said in a statement.

Based on results from the large study, he and his co-authors noted that "[u]nderstanding the inherited basis of T2D will require much further progress in identifying the mechanisms whereby common, mostly non-coding, variants influence disease risk."

In an effort to flesh out T2D genetic architecture and explore potential roles for rarer variants, the researchers began with low-coverage genome sequence data, deep exome sequences, and array-based genotypes for 1,326 individuals with T2D and 1,331 without, all enrolled from northern and central Europe by the GoT2D consortium.

Patterns at 26.7 million SNPs, small insertions or deletions, or large deletions in those individuals led to 126 variants at four loci previously linked to T2D. Through an analysis of the GoT2D samples, alongside imputed genotypes for another 11,645 European cases and 32,769 controls, the team stretched this to 674 suspicious variants at 14 loci. That included one new locus, confirmed through replication testing in more than 115,000 more cases and controls.

The researchers found two more T2D-linked, low frequency variants through an analysis that took into account known T2D loci.

They then analyzed data for the GoT2D individuals in conjunction with exome sequences for 6,504 individuals with T2D and 6,436 controls enrolled from European, South Asian, East Asian, Hispanic, and African American populations for the T2D-GENES study.

From the more than 3 million variants found in these protein-coding sequences, the team found a single variant with genome-wide significant ties to T2D: an alteration in the PAX4 transcription factor gene that was linked to T2D risk in the East Asian population. By analyzing genes near T2D GWAS loci, meanwhile, it uncovered an apparent association near the FES gene that was specific to South Asian individuals.

When they folded in data for 28,305 European cases and 51,549 controls — genotyped with an Illumina exome array designed with help from T2D-GENES data — the researchers identified genome-wide significant T2D associations at a dozen loci known from past GWAS and one new locus.

Along with analyses of the genes affected by such variants, the team modeled the architecture of T2D genetics and began parsing signals from alleles with potential functional roles in T2D risk.

It is making information from its exome, genome, and genotyping analyses available to other researchers through the Accelerating Medicines Partnership's T2D genetics portal.