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Ongoing efforts to define additional common variants influencing traits of biomedical importance are motivated by the biological insights that follow the identification of robust causal relationships between genome sequence variation in a given location and the phenotype of interest. Following the initial success of the genome-wide association effort in finding large numbers of susceptibility loci for type 2 diabetes, further success is going to be increasingly dependent on improvements in efforts to extend these studies to a wider range of variants examined in a wider range of populations.
For type 2 diabetes (T2D), the betes enetics eplication nd eta-analysis (DIAGRAM) consortium has concentrated current efforts on T2D signals in European-descent populations. The Meta-Analysis of Glucose and Insulin-related traits (MAGIC) consortium has focused on variants influencing continuous glycemic traits in non-diabetic individuals. The efforts of these (and other) consortia have contributed to an expansion in the number of confirmed T2D common variant signals to 40, with another 20 or so influencing continuous glycemic traits. At the same time, the results from similar studies conducted in non-European data sets are emerging. These studies are revealing additional loci influencing T2D risk, as well as confirming many of the associations previously reported in European samples. Indeed, there is a great deal of overlap in the common variant GWAS signals for T2D seen in samples collected from different major ethnic groups. This finding argues strongly that the association signals detected by GWAS (which have to date been focused around common variants) are themselves driven by common causal variants that are widely distributed across the globe (most likely since they arose before the spread out of Africa). If so, transethnic fine-mapping approaches should make it possible to narrow down the location of the causal variants, and thereby enhance our ability to connect these association signals with the molecular events through which they influence diabetes risk. I will report on some of our efforts in this respect.
The other way in which the term “global” is relevant here relates to the genome. One of the main challenges in the field right now is to move towards a more complete enumeration of alleles contributing to genetic risk of T2D through extending the spectrum of variants evaluated. Large next-generation sequencing studies now underway should provide the first clues to the roles of low frequency and rare variants to diabetes susceptibility, and again, I will describe some of these studies.
The expectation is that these efforts will allow us to address two further challenges which follow from genetic discoveries. First, we need to move from these association signals to understanding of biological mechanisms through identification of the causal variants driving these effects and the genes and pathways through which they operate; and second, we have a duty to translate these discoveries into advances in clinical management of diabetes. |
