Leif Groop

Rashmi Prasad

Anna Lessmark

The Parent-of-origin genetic effects, imprinting and islet development Action Group

Type 2 diabetes (T2D) is a complex heterogeneous disease resulting from a complex interplay between genetic and environmental factors. Heritability is about transmission of a trait in families. Additionally, the effects of susceptibility variants also depend on which parent they are inherited from. It has often been observed that diabetes is more common in offspring with an affected mother, rather than an affected father. Heritability and sex specific parental effects have been previously reported in the Botnia study wherein a parental history of NIDDM influenced the insulin response to the oral glucose load, with male offspring of diabetic mothers showing the lowest insulin values (1). 

Several GWAS have established a genetic basis for T2D in the form of >65 genetic variants accounting for ~15% of the heritability. However, parental specific transmissions of risk alleles in families have been mostly unexplored and the function of most of these variants unknown. Recent studies based on the Icelandic population have shown a maternal effect of 4 variants including those in KCNQ1 and KLF14 (2). Studies on the molecular mechanisms at the KCNQ1 locus showed a monoallelic expression in the fetal but not adult pancreas (3). Recent studies from our lab reported a maternal effect at the Grb10 locus.
Our aim is to assess the transmission and parent-of-origin effects (POE) of SNPs in risk of T2D and related traits, including glucose metabolism and insulin secretion in families. We aim to achieve this through the implementation of systems biology approaches including a combination of genetic, epigenetic, transcriptomic and functional studies. Our study population comprises of 2 of the largest family based cohorts including the Botnia study and the Hungarian Transdanubian Biobank with altogether > 2200 trios, > 2000 families and 14000 individuals. Islets studies will be performed in human adult pancreatic islets as well as in the fetal pancreas. 

1.    Groop L, Forsblom C, Lehtovirta M, Tuomi T, Karanko S, Nissen M, et al. Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes. 1996;45(11):1585-93. Epub 1996/11/01.
2.    Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S, et al. Parental origin of sequence variants associated with complex diseases. Nature. 2009;462(7275):868-74. Epub 2009/12/18.
3.    Travers ME, Mackay DJ, Dekker Nitert M, Morris AP, Lindgren CM, Berry A, et al. Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in human islets. Diabetes. 2013;62(3):987-92. Epub 2012/11/10.

Last updated: March 13, 2014
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