title: 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 second- and 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.
authors.affiliation: Department of Epidemiology and Biostatistics, Harvard School of Public Health, University of California, Los Angeles, USA. pkraft@hsph.harvard.edu
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Christina G S
authors.initials: CG
authors.lastname: Palmer
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Woodward
authors.forename: Joni A
authors.initials: JA
authors.lastname: Turunen
authors.forename: Sonia
authors.initials: S
authors.lastname: Minassian
authors.forename: Tiina
authors.initials: T
authors.lastname: Paunio
authors.forename: Jouko
authors.initials: J
authors.lastname: Lönnqvist
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
mesh_terms: D001722:Birth Order; D002648:Child; D002675:Child, Preschool; D005260:Female; D005315:Fetal Diseases / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D009035:Mothers; D011247:Pregnancy; D012203:Rh Isoimmunization / Q000150:complications / Q000235:genetics*; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics*; D035781:Siblings