In the current project, genetic determinants of type 2 diabetes mellitus and obesity are being sought using techniques of genetic linkage and association analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available from other families in nuclear pellets extracted from blood specimens obtained in the epidemiologic studies and is amplified by whole genome amplification when needed. An autosomal genome-wide linkage study identified strong evidence for a locus influencing diabetes and diabetes/obesity on chromosomes 1q and 11q. Efforts to identify the causative polymorphism or polymorphisms in both of these regions are currently underway using both a systematic analysis of linkage disequilibrium and analyses of candidate genes. Genome-wide association mapping methods are also being used and exhaustive association analyses are being conducted of regions identified by the genome-wide association studies and of other candidate genes. Whole genome sequencing studies are also being pursued. Genetic variants in the trehalase gene, which is in a region linked to diabeteson chromosome 11q, are strongly associated with plasma trehalase activity and one of these variants is also consistently associated with diabetes. Several candidate genes that have been associated with type 2 diabetes in other populations have been evaluated. The majority of genes seen in other populations appear to have consistent effects in Pimas, though only a few show statistical significance. Some variants identified in other populations (e.g. TCF7L2) appear to have little effect. Variants in established type 2 diabetes genes, MOB2, KLF14 and KCNQ1, are subject to parent-of-origin effects and these parent-of-origin effects replicate in Pimas. The effect of the KCNQ1 variants is particularly strong;with consideration of the parent-of-origin effect these variants account for 4% of liability in susceptibility to diabetes. Recently genome-wide association studies initially with 100,000 markers and later with 1,000,000 markers have identified several additional potential susceptibility genes for young-onset diabetes and for obesity. These include potential diabetes-susceptibility variants in a number of genes and potential obesity-susceptiblity variants in SIM1 and MAP2K3. Replication studies in larger sample sizes are planned, as are functional studies. Variants in candidate genes, such as LEPR, LPGAT1 and SIRT1 show nominally significant association with diabetes, obesity and related traits in Pimas;rare variants in MCR4 are also associated with obesity particularly in childhood. Currently fine-mapping studies with additional variants are being conducted to extract more of the genetic information in regions identified as potentially involved in diabetes susceptibility. Through collaborations, studies are being conducted to determine if any of the signals identified in the present mapping studies replicate in other populations. Variants reproducibly associated with type 2 diabetes from other populations are also being typed to determine their role susceptibilty to diabetes and obesity in the Pimas. Whole genome sequencing is also being conducted in a small number of participants. The data from these studies will initially be used to impute untyped variants from the genome-wide association data;data from these studies suggest that existing reference panels are not accurate for imputation in American Indians. Additional American Indian participants are being recruited for replication studies.

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Billings, Liana K; Jablonski, Kathleen A; Ackerman, Rachel J et al. (2014) The influence of rare genetic variation in SLC30A8 on diabetes incidence and ?-cell function. J Clin Endocrinol Metab 99:E926-30
Hanson, Robert L; Muller, Yunhua L; Kobes, Sayuko et al. (2014) A genome-wide association study in American Indians implicates DNER as a susceptibility locus for type 2 diabetes. Diabetes 63:369-76
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del Rosario, Melissa C; Ossowski, Vicky; Knowler, William C et al. (2014) Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation. Metabolism 63:654-60
Muller, Yunhua L; Piaggi, Paolo; Hoffman, Duncan et al. (2014) Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure. Diabetologia 57:1382-90
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