Fetal programming and parent of origin effects on type 2 diabetes

Background and AimsType 2 diabetes (T2D) has a strong heritable component and shows a preferential maternal transmission. However, GWAS explain ~19% of T2D heritability.

Here, we aim to investigate the missing heritability through parent-of-origin effects (POE) on common variants and rare de novo and loss-of-function mutations, which could explain the maternal transmission and relate to developmental programming.ImplementationA systems genetics approach wherein integrated -omics and machine learning will be applied to genetics (GWAS), epigenetics (global DNA methylation) and transcriptomics (RNAseq) data to investigate POE in trios from large family and population-based cohorts from Sweden, Finland, Hungary, India, Norway, and Tanzania (n>55000).

We will investigate POE specific genetic and epigenetic mechanisms and consequent gene expression modulation in blood from trios. POE will be studied in fetal pancreas through single cell RNAseq, bulkRNAseq, and whole genome bisulfite sequencing. Loci showing POE will also be functionally assessed in adult islets, cord blood, placenta and relevant tissues.

The same loci will be investigated for their role in beta cell development through CRISPR-Cas9 knockdown studies in iPS cell lines (eg.ZFP36L2, RTL1, others).

SignificanceNovel loci discovered would uncover new biology and mechanisms of disease manifestation and explain some of the missing heritability. These will hopefully pave the way for personalized medicine.