RHD Maternal-Fetal Genotype Incompatibility Increases Schizophrenia Susceptibility

• Published in: American journal of human genetics Vol. 71; no. 6; pp. 1312 - 1319
• Main Authors: Palmer, Christina G.S., Turunen, Joni A., Sinsheimer, Janet S., Minassian, Sonia, Paunio, Tiina, Lönnqvist, Jouko, Peltonen, Leena, Woodward, J. Arthur
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-12-2002; University of Chicago Press; The American Society of Human Genetics
• Subjects: Adult; Adult and adolescent clinical studies; Alleles; Biological and medical sciences; Female; Fetus - metabolism; Finland; Genetic Markers - genetics; Genetic Predisposition to Disease; Genotype; Humans; Likelihood Functions; Linkage Disequilibrium; Male; Medical sciences; Models, Genetic; Mothers; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Rh-Hr Blood-Group System - genetics; Schizophrenia; Schizophrenia - genetics; Finland; Psychosis; Human; Incompatibility; Mother; Pathogenesis; Predisposition; Schizophrenia; Fetus; Genotype; Rh-System; Genetic determinism
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/344659

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.