Investigating parent of origin effects in studies of type 2 diabetes and obesity

Abstract

The role of parent-of-origin effects (POE) in the etiology of complex diseases such as type 2 diabetes (T2DM) and obesity is currently of intense interest, but still largely unclear. POE are transmittable genetic effects whereby the expression of the phenotype in the offspring depends upon whether the transmission originated from the mother or father. In mammals, POE can be caused by genetic imprinting, intrauterine effects, or maternally inherited mitochondrial genes. In this paper, we describe the different mechanisms underlying POE, characterize known examples of POE in rare forms of diabetes, and review the evidence from linkage and association studies for POE in T2DM and obesity. Finally, we summarize some of the new and established statistical and experimental approaches commonly used to detect POE. Through this paper, we hope emphasizes the potentially significant importance of POE in the etiology of T2DM and obesity.

Figure 1

Mechanisms of Parent-of-Origin Effects include (A) the influence of the maternal intrauterine environment on gene expression patterns, (B) exclusive maternal inheritance of functional genes in the mitochondrial genome, and (C) differential expression of gene copies depending on from which parent, mother or father, they are inherited (paternally-dependent expression shown). Pathways corresponding to parent-of-origin effects indicated by dashed arrows.

Figure 2

Pedigree depicting a maternally-imprinted, paternally-expressed type 2 diabetes gene. Affected individuals are represented by solid squares and circles. Maternally-inherited alleles are shown in pink, paternally-inherited alleles in blue. The A allele represents a normal functioning copy of the gene and the B allele represents a mutant copy of the gene (also indicated by red “X”). Offspring are affected with type 2 diabetes when the mutant allele B is inherited from the father because the normal maternal copy is also nonfunctional due to silencing by imprinting. If mutant allele B is inherited from the mother, the offspring will be unaffected because the paternal (expressed) copy is normal. Note that for simplification, the mutation shown here is assumed to be fully penetrant and the sole possible cause of the disease, which are not typical assumptions for type 2 diabetes susceptibility genes. Note that individuals 1–5 all have a copy of the mutant allele B. Individuals 2, 3, and 5 received allele B from their father and are therefore affected. In contrast, individuals 1 and 4 received allele B from their mother and are unaffected.