The objective of the research in this application is to identify diabetes-susceptibility genes mapping to chromosome 1q. A 25Mb region of chromosome 1q21-25 has been targeted since it contains an extremely well-replicated type 2 diabetes linkage signal, now detected in scans performed in a range of populations including those of European, East Asian, Native American and African American origin. The hypothesis to be tested is that this replicated linkage reflects the action of one or more susceptibility genes capable of influencing the inherited predisposition to type 2 diabetes in multiple ethnic groups. The strategy to be adopted combines systematic, high-density linkage disequilibrium mapping with exhaustive examination of selected positional candidates. The proposal comes from a unique international consortium that allies clinical and basic investigators representing populations with the strongest evidence for 1q linkage with expertise in high-throughput genomics, informatics and statistics from leading groups in the International HapMap project. This consortium is therefore powerfully-placed to apply the latest developments in genotyping technology, informatics and the understanding of human sequence variation to analysis of unparalleled clinical resources. Analysis of preliminary data from 3000 1q SNPs typed for over 4000 samples has already identified several genes showing replicated associations with diabetes.
Our specific aims are: 1. to complete the indirect linkage disequilibrium survey of the entire 1q region of interest through a final round of genotyping designed to ensure comprehensive capture of the effects of common variation; 2. to follow up the association signals detected through analysis of further SNPs and larger clinical samples; 3. to integrate the association data obtained in its biological context through development of dedicated informatics tools, and to use these tools to enable a systematic evaluation of the biological candidacy of regional transcripts and to support a search for polymorphic duplications; 4. to undertake direct, comprehensive analysis of the genes so identified to characterize etiological variants. Identification of the specific variant(s) responsible for the linkage signal will enhance our understanding of the fundamental molecular events involved in the development of type 2 diabetes. This information will contribute to future diagnostic and therapeutic advances in the clinical management of this condition. ? ? ?
|Scott, Robert A; Scott, Laura J; Mägi, Reedik et al. (2017) An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes 66:2888-2902|
|Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji et al. (2015) Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat Genet 47:1415-25|
|van de Bunt, Martijn; Gaulton, Kyle J; Parts, Leopold et al. (2013) The miRNA profile of human pancreatic islets and beta-cells and relationship to type 2 diabetes pathogenesis. PLoS One 8:e55272|
|Randall, Joshua C (see original citation for additional authors) (2013) Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. PLoS Genet 9:e1003500|
|Morris, Andrew P; Voight, Benjamin F; Teslovich, Tanya M et al. (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44:981-90|
|Yang, Jian; Loos, Ruth J F; Powell, Joseph E et al. (2012) FTO genotype is associated with phenotypic variability of body mass index. Nature 490:267-72|
|Hu, Cheng; Zhang, Rong; Wang, Congrong et al. (2011) Lack of association between genetic polymorphisms within DUSP12 - ATF6 locus and glucose metabolism related traits in a Chinese population. BMC Med Genet 12:3|
|Heid, Iris M (see original citation for additional authors) (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42:949-60|
|Voight, Benjamin F; Scott, Laura J; Steinthorsdottir, Valgerdur et al. (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579-89|
|Qin, Wen; Zhang, Rong; Hu, Cheng et al. (2010) A variation in NOS1AP gene is associated with repaglinide efficacy on insulin resistance in type 2 diabetes of Chinese. Acta Pharmacol Sin 31:450-4|
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