Functional genomics approaches to dissect causal DNA variations in obesity and type 2 diabetes

Abstract: GWAS studies have identified hundreds of loci that associate with obesity and type 2 diabetes. However, the functional relevance of the genetic variants, and their impact on disease or traits, is largely unknown. To address those questions, we applied functional genomics approaches to study genetic variants pertinent to obesity and type 2 diabetes-related traits.In paper I, we demonstrate that rs67785913 is a causal cis-eQTL for MTIF3 expression. We also show that MTIF3 regulates mitochondrial respiration and endogenous fatty acid oxidation in adipocytes, probably as a consequence of MTIF3 affecting mitochondrial oxidative phosphorylation complex assembly. MTIF3 deficiency also leads to higher retention of triglycerides after glucose restriction challenges. In paper II, we show that rs8192678 confers allele-specific causal effects on white adipocyte differentiation. The T allele presents a dose-dependent effect on increased lipogenesis and mitochondrial function, and on the expression of genes involved in adipogenesis, lipid catabolism, lipogenesis, and lipolysis. The T allele also confers higher levels of PPARGC1A mRNA and PGC-1α protein, as well as faster turnover and higher activity of PGC-1α. In paper III, we experimentally document that rs10071329 is a cis-eQTL for PPARGC1B expression, and influences brown adipocyte lipolysis and mitochondrial function. In a Tanzanian cohort lookup, rs10071329 shows a trend of association for BMI, and an association with mid-upper arm circumference. In paper IV, we show that allele substitution at rs2289669 and rs8065082 does not affect SLC47A1 expression or splicing in HepG2 cells. Moreover, among MetGen cohort participants, we observed that no common genetic variants in SLC47A1 were associated with metformin-mediated efficacy on glycemia reduction.The findings presented in this thesis provide biological mechanistic insights underlying epidemiological observations and may aid in developing precision medicine for obesity and type 2 diabetes.