Recent whole-genome association studies (WGA) using large-scale genotyping arrays have provided evidence that common genetic variation contributes to obesity, type II diabetes and myocardial infarction. Nonetheless, the so far confirmed 19 metabolic disorder related loci explain only less than 10% of the genetic contribution to these diseases. The degree of genome coverage provided in these studies was ~80% of the common variation in the genome (a minor allele frequency, MAF >5%); but only ~0.01% of the diploid genome and <1% of the known causative (deleterious) alleles, which are individually rare but collectively common was covered. Even though a new generation of genotyping arrays including 1-1.8 million SNPs were launched in 2007, it is not so promising that the remaining genetic variation will be identified; at best 5-10 common variants with low penetrance will be identified, leaving the majority of genetic variation contributing to type 2 diabetes susceptibility are shrouded in the unknown.
Since 2006, there have been several technical breakthroughs in DNA sequencing, and Now-Gen sequencing technology achieves multiple Gb of data per run at the cost that are orders of magnitudes lower than before. Thus, this now-generation large-scale sequencing technology provides a novel chance to identify both novel rare and common genetic variation, which are necessary to explain the remaining ~90% of the genetic contribution to type 2 diabetes and related metabolic and cardiovascular disorders.
A novel approach that balances the benefit of now-generation large-scale and still fairly expensive re-sequencing cost is to sequence the coding parts of the genome (exons, including 5’- and 3’ UTRs). To catch up this chance and to make best use of international resources, a LuCAMP consortium of 10 research organizations from Europe and China was formed to carry out this project. By sequencing 3,000 patients with gender-defined visceral obesity who in addition suffer from type 2 diabetes and essential hypertension and 3,000 age- and gender-matched, glucose-tolerant, lean and normotensive individuals we will: (1) identify novel rare and common genetic variation, and (2) identify differences in allele frequency of novel and known genetic variation between patients with pre-vascular metabolic disorders and healthy controls, i.e. a focused approach on the genetics of obesity, type 2 diabetes and hypertension. One of the most attractive scenarios with the sequencing approach is that 1,536 top-hit SNPs, i.e. SNPs with the largest difference between the case-control pools, will be replicated on genotyping arrays that are custom made for type 2 diabetes, obesity and hypertension.
LUCAMP gathers 9 Danish university centers/institutes and BGI from China in the purpose of clinical translation of research discoveries to patients for new personalized interventions and ongoing large-scale observational studies and clinical trials.