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T2D-GENES, GoT2D Consortia Offer Updates on Searches for T2D Contributors at ASHG

SAN FRANCISCO (GenomeWeb News) – A pair of large, international consortia are cranking out reams of genome, exome, and genotyping data in the hopes of expanding and refining their understanding of the genetic factors behind type 2 diabetes and traits related to it.

Each of the groups provided information on the strategies they are using to reach that goal — and the progress made so far — in several talks and posters presented at the American Society of Human Genetics annual meeting held here last week.

One of the teams is working on a three-pronged study known as the "Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples," or T2D-GENES. That effort involves a massive exome sequencing arm being done in five populations, a deep genome sequencing study centered on a very large, multigenerational family, and a fine-mapping analysis of known T2D loci.

The other project, being carried out by the "Genetics of T2D," or GoT2D, consortium also involves genome sequencing, exome sequencing, and other analyses, though the approach being used is somewhat different. There, researchers are bringing together low-coverage genome sequence data, deep exome sequences, and genotyping information for nearly 3,000 individuals from four well-characterized European cohorts.

Tens of thousands more individuals will be assessed through exome chip genotyping as part of GoT2D's effort to find new low-frequency variants in new or known genes that confer moderate to relatively high T2D risk.

Within both the T2D-GENES and GoT2D studies, there is also interest in identifying causal SNPs at known loci and in finding genetic contributors to quantitative traits that are related to T2D risk such as blood lipid profiles or fasting insulin or glucose levels.

From the T2D-GENES consortium, for instance, University of Michigan biostatistics and statistical genetics researcher Tanya Teslovich presented information on the team's preliminary analyses of the first 5,300 or so individuals to have their exomes sequenced — part of the T2D-GENES effort to sequence 10,000 exomes from five ancestry groups. Teslovich is leading that arm of the study in conjunction with Andrew Morris from the University of Oxford Wellcome Trust Centre for Human Genetics.

Collaborators at the Broad Institute are generating the exome data using Illumina instruments and a standardized sequencing pipeline and expect to have exome sequences for all 10,000 individuals by early next year.

These exomes come from 5,000 T2D cases and as many unaffected controls enrolled through 10 cohorts from African American, East Asian, European, Hispanic, and South Asian populations, allowing a look at the genetic contributors to T2D and relevant traits both across populations and within each population.

For instance, Teslovich noted that the T2D-GENES team's initial analyses have uncovered a variant in PAX4, a gene known for its role in pancreatic islet beta cell development, that appears to be associated with T2D specifically within the East Asian population. The same variant has been implicated in early diabetes onset in previous studies, she noted, though the T2D-GENES group has found no ties between the PAX4 variant and earlier-than-usual T2D diagnosis in their own data.

So far, the exome sequencing study has not unearthed any low-frequency variants with significant links to T2D, though researchers are optimistic that that could change once they include all 10,000 exomes in the analyses, which should bump up the power to detect associations.

"We anticipate that analysis of the full dataset will lead to identification of causal genes and variants and give insight into the genetic architecture of T2D," Teslovich, Morris, and their colleagues wrote in the abstract accompanying the ASHG presentation.

Another branch of the T2D-GENES is doing fine mapping of known T2D loci implicated through past genome-wide association studies, while a third arm of the project involves deep whole-genome sequencing on roughly 1,110 individuals from 20 large, multi-generational Mexican-American families.

As GenomeWeb Daily News sister publication Clinical Sequencing News reported previously, Complete Genomics has already cranked out data for 600 or more of those genomes, which are each being sequenced to around 60-fold coverage, on average.

By the end of 2013, researchers are also aiming to bring together data for all of the genomes and exomes assessed through T2D-GENES and GoT2D, University of Oxford researcher Mark McCarthy, who is involved in both consortia, said at a meeting with reporters last week.

At the moment, GoT2D researchers are continuing to build their integrated dataset, which includes 4X whole-genome sequence data, deep exome sequence data, and genotype information at millions of SNPs for 2,850 Europeans with or without T2D. They are also planning to impute genotyping data for another 30,000 individuals and to genotype some 50,000 individuals using an exome chip approach.

The integrated dataset is expected to allow for a more or less complete ascertainment of low frequency SNPs in the European population, GoT2D consortium member Jason Flannick, a medical and population genetics researcher from the Broad Institute, said during another ASHG presentation.

At this point, Flannick said the GoT2D researchers have not identified low-frequency variants — namely, those present as few as 1.5 percent of European individuals — that increase T2D risk by three times or more over the typical population risk. But they have been able to better characterize specific loci linked to T2D through past GWAS and are identifying variants that seem to influence T2D-related quantitative traits such as low-density lipoprotein cholesterol levels.

Going forward, members of the GoT2D team say their final European dataset should make it possible to assess not only common and low-frequency variants, but also small insertions and deletions and structural variants.

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