Distinct types of parent-of-origin mechanisms tested in this study.

Fig. 1a. Genomic imprinting: Genomic imprinting is characterized by consequent silencing of one allele, depending on the parental origin. In the example shown above a normal situation is displayed on the left and the genomic imprinting is shown on the right; red is the risk allele and bleu is the wild type allele. The maternal genotype is heterozygous, the father’s genotype is homozygous wild-type. Offspring in the left scenario have a normal phenotype since the paternal wild-type allele is expressed in the heterozygous offspring and the mutated allele of the mother is thus rescued by the paternal allele. On the right genomic imprinting is shown, reflecting the α-term in the method used to test for parent of origin effects. In this example there is a significant genomic imprinting effect and the OR >1 so the paternal allele is silenced (see materials and methods section statistical analysis). We assume an additive or recessive model of inheritance. Two possible outcomes are listed, if the offspring inherits the risk allele from the mother and the wild-type allele from the father is subjected to genomic imprinting, then only the risk allele is expressed, thus the offspring is affected by the mutated allele from the mother. Fig. 1b. Maternal effects: Maternal effects are effects of the maternal genotype on the fetal phenotype, irrespective of the fetal genotype, these effects are reflected by the β- and γ-terms in the likelihood ratio test that was used to test for parent of origin effects in our study. In the example given above, the β- and γ-terms are significant with an OR >1, meaning that the risk of disease is higher if the mother carries two or one risk allele respectively. A recessive or co-dominant model is assumed, and higher expression of the mutant allele leads to disease. If the genotype of the offspring is red, then maternal effects cause increased disease risk and if it is green than the normal population risk applies. If the mother is homozygous wild-type, no maternal effects occur. If she is homozygous mutant or heterozygous for the risk allele, the offspring is subjected to maternal effects and thus has an increased disease risk. Note that the wild-type homozygous offspring has a higher disease risk if both parents are heterozygous.