Hjelt grant holder 2019, Lund university
Precision medicine in Type 2 Diabetes
Type 2 diabetes (T2D) is the fastest growing global epidemic with worldwide prevalence estimates of 382 million people living with diabetes in 2013 and 592 million by 2035. T2D is caused by a complex interplay of genetic and environmental factors. While T2D has shown strong heritability, variants discovered through case control based GWAS studies have only been able to explain a small proportion (~15%) of the heritability. In the current proposal, we aim to use novel approaches to identify this undetermined component of heritability, referred to as missing heritability, of T2D.
It has been observed that T2D is seen more often in offspring of T2D mothers rather than fathers. This could be attributed to parent-of-origin effects, wherein the phenotypic effect of the allele depends on its parental origin; Therefore, a preferred maternal or paternal transmission of risk genotypes is observed, accompanied by differential epigenetic programming (where the DNA code is unchanged but the reading is affected by environmental factors) of paternal and maternal alleles and gene expression discordance. This could also relate to fetal programming during the intrauterine period. Conventional GWAS studies using case-control design could miss such effects.
We will here use global genetic, epigenetic and transcriptomic data from large family cohorts to identify such effects. Subsequently, we will explore whether these loci affect gene expression in a parent of origin manner in relevant adult and fetal tissues – pancreas, liver, kidney, muscle, adipose tissue, placenta and cord blood to understand their role in fetal programming and development as well as relationship to diabetes in later life.
Another source of missing heritability could be de novo mutations. An estimated 70 new mutations arise in the human diploid genome each generation. The role of de novo mutations in diabetes has however been largely unexplored, mostly because of lack of family materials. We will, in this project also investigate de novo mutations as well as their parental specific transmissions and association with diabetes.
New genetic risk variants can help us understand the biology of the disease and point to new mechanisms that lead to disease development.