RHD maternal–fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order

Abstract

Rh incompatibility disease (ie Rh hemolytic disease of the fetus and newborn) has been implicated as a risk factor for schizophrenia. Here, we extend the maternal -fetal genotype incompatibility (MFG) test used in an earlier case-parent trio study that found significant evidence for an increased risk of schizophrenia in RHD MFG-incompatible children. We modify the MFG test for case-parent trios to include any number of siblings. This modified test enables us to use more of the available data from the earlier study. The increased sample size not only gives us greater power to test for MFG incompatibility but it also enables us to model the impact of previous RHD MFG-incompatible pregnancies on the relative risk of RHD MFG incompatibility in later-born siblings. This modeling is important, because RHD MFG incompatibility is a proxy for Rh incompatibility disease, and the risk of Rh incompatibility disease increases with the number of previous RHD MFG-incompatible pregnancies. The best-fitting models are consistent with the hypothesized effect that previous incompatible pregnancies increase the risk of schizophrenia due to RHD MFG incompatibility. There was significant evidence that the relative risk of schizophrenia in the secondand later-born RHD MFG-incompatible children is 1.7, consistent with earlier estimates. Our extension of the MFG test has general application to family-based studies of maternal-genotype and MFG interaction effects.

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

“…Although this is the first study assessing serious OCs as the environmental risk factor with polymorphisms in specific selected genes, other studies have shown plausible evidence for gene-byenvironment interaction playing a role in schizophrenia risk, 28,34,35 especially mother-child blood group incompatibility. [36][37][38][39] Although our results are exploratory, they support the long-held view of serious obstetric complications interacting with specific genetic risk factors to increase risk for schizophrenia. Our data also have broader implications for finding association between the genes explored in this study and schizophrenia in general clinical samples.…”

Incorporating Serotypes into Family Based Association Studies Using the MFG Test

“…Then we model the specific example of Rhesus D MFG incompatibility, where a maternal allogenic reaction can lead to an adverse environment for the developing fetus (see as examples, Strachan & Read, 1999;Palmer et al 2002), using RHD genotypes and RHD serotypes. Kraft et al (2004) introduced a version of the MFG model that calculates the likelihood of the maternal, paternal, and children's codominant genotypes conditional on the affected children. The likelihood for a single family's genotypes is…”

“…The likelihood (1) can be modified to include siblings who are unaffected or have unknown phenotypes (Kraft et al 2004). The likelihood for a single nuclear family's serotypes is similar to equation (1) except that we need to sum over the missing codominant genotypes,…”

Combined linkage disequilibrium and linkage mapping: Bayesian multilocus approach

“…Whenever possible, we recommend testing for departures from random mating in a sample of randomly ascertained parent pairs from the same population as the study sample. When a severe violation of random mating is observed, use the nuclear-family version of the MFG test that does not assume random mating [50,92]. Alternatively, consider the case-mother, control-mother approach [17].…”