RHD Maternal-Fetal Genotype Incompatibility Increases Schizophrenia Susceptibility

Abstract

Fetal events and obstetric complications are associated with schizophrenia. Here we report the results of a family-based candidate-gene study that assesses the role of maternal-fetal genotype incompatibility at the RHD locus in schizophrenia. We adapted the case-parent-trio log-linear modeling approach to test for RHD maternal-fetal genotype incompatibility and to distinguish this effect from a high-risk allele at or near the RHD locus and from a direct maternal effect alone. Eighty-eight patient-parent trios, 72 patient-mother pairs, and 21 patient-father pairs were genotyped at the RHD locus. Of the 181 patients, 62% were male and 81% were second born or later. Only three patients were born after prophylaxis against maternal isoimmunization had become common practice. There was significant evidence for an RHD maternal-fetal genotype incompatibility, and the incompatibility parameter was estimated at 2.6. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus nor any evidence to support the role of maternal genotype effect alone. Our results replicate previous findings that implicate the RHD locus in schizophrenia, and the candidate-gene design of this study allows the elimination of alternative explanations for the role of this locus in disease. Thus, the present study provides increasing evidence that the RHD locus increases schizophrenia risk through a maternal-fetal genotype incompatibility mechanism that increases risk of an adverse prenatal environment (e.g., Rh incompatibility) rather than through linkage/association with the disorder, linkage disequilibrium with an unknown nearby susceptibility locus, or a direct maternal effect alone. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia.

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

“…In this section, we develop the underlying statistical model in its full generality, for nuclear families and for case-parent trios. 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.…”

“…A maternal allogenic response that is detrimental to the fetus occurs if the d/d mother recognizes the fetal RhD antigen as nonself. We use μ to parameterize the increased relative risk of disease when the mother is d/d and child is D/d (Palmer et al 2002;Sinsheimer et al, 2003). The expected values for each trio combination under the MFG model with codominant RHD genotypes are given in Table 1.…”

“…The ability to use serotypes is important because obtaining codominant RHD or ABO genotypes that fully reflect the antigenic properties that can produce the adverse prenatal environment (such as developed by Wagner & Flegel (2000) and used by Palmer et al (2002) in the case of RHD) is not routine, and certainly has not yet replaced RhD or ABO serotyping. In fact, in his recent review article on the use of molecular methods to determine blood types, Daniels (2004, p. S66) states that 'It is unlikely that molecular methods will replace routine serological ABO and RhD testing of patients and donors in the foreseeable future.'…”

“…The explicit inclusion of the mating type parameters readily allows the use of incomplete data in the MFG model. As examples, Weinberg (1999a) and Palmer et al (2002) showed that parentchild dyads could be considered parent-child trios with missing parental genotype data and, using the MFG test, demonstrated that these dyads could be included in analyses of disease-increasing effects of loci. When complete parental genotypes are available, it is also possible to condition upon parental genotypes or mating types when modeling the distribution of codominant genotypes, thus eliminating the mating type parameters from the likelihood (Schaid & Sommer, 1994;Cordell 2004;Cordell et al 2004;Minassian et al 2005).…”