Genomes and Genes
The international 1q type 2 diabetes consortium
Principal Investigator: MARK IAN MCCARTHY
Affiliation: University of Oxford
Abstract: 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 performedin a range of populations including those of European, East Asian, Native Americanand African Americanorigin. The hypothesis to be tested is that this replicated linkage reflectsthe 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 comesfrom 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 disequilbrium 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.
Funding Period: ----------------2006 - ---------------2012-
more information: NIH RePORT
- Variants in ARHGEF11, a candidate gene for the linkage to type 2 diabetes on chromosome 1q, are nominally associated with insulin resistance and type 2 diabetes in Pima IndiansLijun Ma
Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ 85004, USA
Diabetes 56:1454-9. 2007..01). These findings suggest that variation within ARHGEF11 nominally increases risk of type 2 diabetes, possibly as a result of increased insulin resistance...
- The miRNA profile of human pancreatic islets and beta-cells and relationship to type 2 diabetes pathogenesisMartijn van de Bunt
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
PLoS ONE 8:e55272. 2013..In conclusion, we have described the miRNA profile of human islets and beta-cells and provide evidence linking islet miRNAs to T2D pathogenesis...
- FTO genotype is associated with phenotypic variability of body mass indexJian Yang
University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia
Nature 490:267-72. 2012....
- Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetesAndrew P Morris
Wellcome Trust Centre for Human Genetics, University of Oxford, UK
Nat Genet 44:981-90. 2012..Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis...
- Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traitsJoshua C Randall
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
PLoS Genet 9:e1003500. 2013..The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits...
- Investigating parent of origin effects in studies of type 2 diabetes and obesityEvadnie Rampersaud
Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, MD, USA
Curr Diabetes Rev 4:329-39. 2008..Through this paper, we hope emphasizes the potentially significant importance of POE in the etiology of T2DM and obesity...
- Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes: association analyses in 9,518 subjectsKatharine R Owen
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, U K
Diabetes 56:879-83. 2007..However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001)...
- Evidence that Rho guanine nucleotide exchange factor 11 (ARHGEF11) on 1q21 is a type 2 diabetes susceptibility gene in the Old Order AmishMao Fu
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Diabetes 56:1363-8. 2007..These results, coupled with similar findings in Pima Indians, suggest that sequence variation in ARHGEF11 may influence risk of type 2 diabetes...
- Variants in the Ca V 2.3 (alpha 1E) subunit of voltage-activated Ca2+ channels are associated with insulin resistance and type 2 diabetes in Pima IndiansYunhua Li Muller
Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, 455 North 5th St, Phoenix, AZ 85004, USA
Diabetes 56:3089-94. 2007..CACNA1E encodes the voltage-dependent calcium channel Ca(v)2.3 Ca(2+), and mice lacking this channel exhibit impaired glucose tolerance and insulin secretion. Therefore, CACNA1E was investigated as a positional candidate gene...
- An evaluation of the performance of HapMap SNP data in a Shanghai Chinese population: analyses of allele frequency, linkage disequilibrium pattern and tagging SNPs transferability on chromosome 1q21-q25Cheng Hu
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People s Hospital, 600 Yishan Road, Shanghai, 200233, China
BMC Genet 9:19. 2008....
- Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1qInga Prokopenko
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
Diabetes 58:1704-9. 2009..We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal...
- Lack of association between genetic polymorphisms within DUSP12 - ATF6 locus and glucose metabolism related traits in a Chinese populationCheng Hu
Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People s Hospital, Shanghai, PR China
BMC Med Genet 12:3. 2011..Studies in Pima Indian, Caucasians and African Americans identified several SNPs in DUSP12 and ATF6, located in chromosome 1q21-q23, were associated with type 2 diabetes...
- Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locusChristopher G Bell
Medical Genomics, UCL Cancer Institute, University College London, London, United Kingdom
PLoS ONE 5:e14040. 2010....
- Association of the POU class 2 homeobox 1 gene (POU2F1) with susceptibility to Type 2 diabetes in Chinese populationsM C Y Ng
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
Diabet Med 27:1443-9. 2010..We examined the association of POU2F1 genetic variants with Type 2 diabetes in Hong Kong Chinese using two independent cohorts...
- Association analyses of 249,796 individuals reveal 18 new loci associated with body mass indexElizabeth K Speliotes
Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
Nat Genet 42:937-48. 2010..Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation...
- Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distributionIris M Heid
Regensburg University Medical Center, Department of Epidemiology and Preventive Medicine, Regensburg, Germany
Nat Genet 42:949-60. 2010..9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions...
- A common variant of NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetesJ Lu
Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center of Diabetes, Shanghai, China
Diabet Med 27:1074-9. 2010..The aim of the study was to investigate the association of polymorphisms of the nitric oxide synthase 1 adaptor protein (NOS1AP) gene with QT interval in Chinese subjects with or without Type 2 diabetes...
- Twelve type 2 diabetes susceptibility loci identified through large-scale association analysisBenjamin F Voight
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
Nat Genet 42:579-89. 2010..We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits...
- A variation in NOS1AP gene is associated with repaglinide efficacy on insulin resistance in type 2 diabetes of ChineseWen Qin
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People s Hospital, Shanghai 200233, China
Acta Pharmacol Sin 31:450-4. 2010..To investigate a potential association between SNP rs10494366 in the neural nitric oxide synthase adaptor protein (NOS1AP) and efficacy of repaglinide (an insulin secretagogue) in newly diagnosed Shanghai Chinese type 2 diabetes patients...
- Hundreds of variants clustered in genomic loci and biological pathways affect human heightHana Lango Allen
Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX1 2LU, UK
Nature 467:832-8. 2010....