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Large-Scale Metabochip Studies ID New Susceptibility Loci for Glycemic Traits and Diabetes

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Two large meta-analyses published this month have taken advantage of a recently developed Illumina array, the Metabochip, to identify new loci influencing a variety of glycemic traits and the pathophysiology of type 2 diabetes.

The reports, from two European consortia, appeared in the same issue of Nature Genetics earlier this month. One study — a report from the Diabetes Genetics Replication and Meta-analysis, or DIAGRAM, consortium — combined earlier genome-wide association data with an additional meta-analysis of 22,000 cases and 58,000 controls genotyped with Metabochip. The other study, from a group called the Meta-Analyses of Glucose and Insulin-related traits, or MAGIC, consortium, also combined new data using Metabochip with earlier results to identify new genomic associations with non-diabetes glycemic traits.

Ines Barroso, the lead author of the MAGIC consortium's report, told BioArray News in an e-mail that members from both groups were involved in creating the Metabochip, a custom genotyping array developed to follow up on large-scale studies of a range of "cardiometabolic" traits or disorders. In addition to the DIAGRAM and MAGIC teams, researchers from seven other research consortia contributed to the design of the chip.

Both studies published this month used the new chip "with the aim to identify additional genetic variants that help explain the genetic influence on both continuous glycemic traits as well as those that influence disease risk directly," Barroso said. "We wanted to explore in more detail the genetic architecture or landscape of each of these traits."

The Metabochip, an Illumina custom iSELECT array, tests approximately 200,000 SNPs identified through genome-wide association studies for metabolic and atherosclerotic/cardiovascular diseases and traits. According to the two groups, the chip covers about 66,000 SNPs selected to enable genotyping of the most significant association signals for 23 different metabolic traits, and another 120,000 SNPs for fine mapping of established loci.

Some of the researchers behind the Metabochip's design described the creation of the array in a separate paper in PLoS Genetics this month. "The need for follow-up genotyping is a frequent requirement of [genome-wide association] and sequencing studies of complex human traits. Approaching array design in a coordinated fashion across related studies and traits can be particularly cost-effective," the group wrote.

"Pooling together information on variants that each consortia wanted to follow up and designing one custom-made chip facilitated the generation of an affordable technology that could then be applied to many thousands of samples to identify additional genetic variants influencing a host of cardiometabolic traits and ultimately could influence risk of diseases such as type 2 diabetes, cardiovascular disease, [and] obesity," Barroso explained in her e-mail.

According to the PLoS Genetics report, a custom chip designed to genotype only the 22,000 SNPs selected for the Metabochip by the DIAGRAM group would have cost about $55 per sample vs. the Metabochip's $39 cost.

In their two recent studies, Barroso's MAGIC team and the DIAGRAM group both found new genetic variants after employing the Metabochip to supplement data from earlier consortium studies.

The MAGIC team reported that adding genotype data covering the Metabochip's 66,000 additional SNPs to previous data identified 38 new loci, increasing the number of known loci influencing glycemic traits to 53, of which 33 show an overlap with type 2 diabetes risk.

The DIAGRAM group also found ten previously unreported loci associated with susceptibility to type 2 diabetes, including two loci showing sex-differentiated association, the researchers reported.

Barroso said in her e-mail that "both papers demonstrate that there is overlap in the genetic determinants of type 2 diabetes and underlying glycemic traits but they also show that the overlap is incomplete."

The DIAGRAM group reported in its paper that exploration of its newly expanded set of diabetes-associated loci revealed several biological processes and pathways — including CREBBP-related transcription, adipocytokine signaling, and cell cycle regulation — potentially implicated in the pathogenesis of the disease.

MAGIC, meantime, said its data suggest a greater than previously identified overlap between loci influencing common glycemic traits and those conferring diabetes risk.

Overall, Barroso said, "both papers support the idea that there are many common genetic variants with small effect sizes that contribute to the risk of diabetes and/or influence glycemic traits and that these variants may account for a significant proportion of the heritability of each of these."

"Both studies are identifying loci, and particular networks and pathways involved in the regulation of blood glucose levels and other traits that will help us improve our understanding of how these all interplay to regulate glycemic traits and also to improve understanding of how things can go wrong in type 2 diabetes," she wrote.

According to the MAGIC consortium's report, the influence of many consortia on the design of the Metabochip was likely a boon to both analyses. In particular, the MAGIC team found that some loci found in the recent study at genome-wide significance levels were not nominated for the chip by the team itself, but rather by other consortia that contributed to its design.

According to the authors of the PLoS Genetics paper on the Metabochip design, two of the ten novel type-2 diabetes loci the DIAGRAM group identified were also placed on the chip for other traits.

Barroso added that both groups found themselves still constrained by sample size, finding some loci that didn't meet genome-wide significance to merit association with a given trait beyond a reasonable doubt. The groups believe that associations that don't reach this level of statistical robustness may still be likely to harbor legitimate "association signals," and should be considered in future studies, the MAGIC team wrote in its report.

According to Barroso, additional studies using Metabochip by the other consortia that collaborated on its design are still ongoing. Additionally, she said, both MAGIC and DIAGRAM are still working on data generated with the chip, "namely in using the Metabochip to help refine or fine-map established association signals."

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