Genome-wide association study (GWAS) and Candidate Associated study in Uruguay Population to identify common and novel susceptibility loci for type 2 diabetes mellitus (T2D)

Population Genetics 633: Final Research Proposal for class

One of the largest epidemics of the 21st century is type-2 diabetes (T2D), a chronic disease characterized by a decrease in tissue sensitivity to insulin. Uruguay is a unique population for not carrying out genome-wide association study (GWAS) even though they have an increased susceptibility to diabetes and have increased insulin resistance. The specific objective of this research is: 1) to identify common genetic variants underlying the risk of T2D in the Uruguay population using GWAS and 2) to test provisory implicated genes in T2D using a candidate gene association study.

For objective one, stage one of the GEWAS approach includes a GWAS scan on alleles with SNP call rate >95% (minor allele frequency >1%) in Uruguay Population with 5,450 cases with T2D 12,550 controls. Then in stage two, replication testing of 20-30 SNPs will be done, followed by sequencing, linkage disequilibrium structure analysis and eQTLs in stage three. Another approach in this study for objective 2 includes a candidate genes association study based on T2D-associated genes from literature (Barroso et al., 2003) using 500 cases and controls. First, SNPs and haplotypes associated with diseases will be identified and tested using a genetic Model showing association with disease in a case-control study. Then we will test SNPs and Haplotypes associated with Disease in QT scenarios of body mass index (BMI), fasting glucose, and fasting insulin.

Results of this research proposal can shed light on whether there was heterogeneity of effect between the Uruguay population and other Europeans. We expect some loci to show a consistent direction of effect in the Uruguay population and Europeans and the remaining loci to be associated with T2D at P < 0.05 in only the Uruguay population.

References:

Borse, S. P., Chhipa, A. S., Sharma, V., Singh, D. P., & Nivsarkar, M. (2021). Management of Type 2 Diabetes: Current Strategies, Unfocussed Aspects, Challenges, and Alternatives. In Medical Principles and Practice (Vol. 30, Issue 2). https://doi.org/10.1159/000511002