American Indians have extremely high rates of T2D, diabetic nephropathy and obesity, yet large-scale sequencing efforts to identify disease loci have not included individuals from this ethnic group. Therefore, variants that are unique or enriched for in American Indians, which may identify new therapeutic targets for these diseases, remain largely unknown. To identify common variation that increases susceptibility to type 2 diabetes (T2D) and/or obesity, whole genome sequence data was generated on 335 Pima Indians. Sequencing was performed by Illumina (N=301) and Complete Genomics, Inc (N=34). 13 million variants were found, including 11 million SNPs, 1.6 million Indels and 255,802 substitutions. Among all SNPs, 2.7 million were novel. To obtain information on rare variants which could potentially have a large effect size on disease risk, we recently obtained whole exome sequence data on 8500 American Indians informative for type 2 diabetes, obesity, diabetic nephropathy and lipid levels . Based on information obtained from whole genome sequencing, we designed an entirely custom Affymetrix Axiom array based on all variation detected in the Pima Indian genomes. This array was initially utilized to genotype 3,637 full heritage Pima Indians who had participated in a longitudinal study of T2D (Stage 1) and 548,206 variants were successfully analyzed which tagged 92% of the 4.9M common variants (minor allele frequency >0.05) detected in the Pima genomes. An additional 4,060 non-full heritage Pima Indians from the same longitudinal study were subsequently genotyped with the array (Stage 2). Among the top associations was a new signal for T2D that had not been captured in our prior genome-wide assocation study which used a commerciallly available genotyping array (Affymetrix 6.0). This SNP (rs11564707)independently associated with T2D in the full heritage (risk allele G frequency=0.45) and non-full heritage (G=0.40) Pima Indian samples (full heritage P=8x10-7; OR95%CI=1.331.19-1.49 and non-full heritage P=5x10-3; OR= 1.221.10-1.40, adjusted for age, sex, birth year, family membership, reported heritage and fraction Indian). Combining the two samples provided the most robust association with T2D (2.2x10-8, OR=1.281.18-1.40), but this association was entirely driven by the 4,175 females (adjusted P=2.5x10-9; OR=1.411.26-1.58); no association was observed in 3,314 males (P=0.14; OR= 1.110.97-1.27). The gender x genotype interaction was significant (P=0.001). This female specific association was also observed for measures of early insulin secretion assessed in full heritage Pima Indians who were normal glucose tolerant. Both the 30 minute insulin levels during a 75g oral glucose tolerant test and the insulin response to a 25g intravenous glucose bolus were reduced in females (both p<0.01) but not males. Rs11564707 maps near the microRNA 4686 and the upstream region of the TH gene and tags 11 nearby variants with an r2>0.99 (including a novel T>TTTTGTTTG insertion at chr11:2,204,322). TH encodes tyrosine hydroxylase which is a good physiologic candidate for this association; however, future functional studies are required to establish the causative variant and affected gene. For the whole exome sequence data, approximately 1.7 million variants were detected in 8500 American Indians. Among these variants, 95% were single nucleotide polymorphisms and 5% were short insertions or deletions. Approximately 493,0000 of these variants occurred in at least 5 subjects, and these underwent single variant analysis for type 2 diabetes and BMI. In addition, gene based models(Burden and SKAT methods) were also employed. The most significantly associated gene variants with diabetes were within the gene transglutaminase 2 (TGM2). This gene is currently undergoing extensive functional assessment.