It is highly likely that some non-Mendelian mechanism involving environmental and genetic factors gives rise to schizophrenia. Current research is providing compelling evidence that one environmental factor, which acts prenatally to increase susceptibility to this disorder, arises from a maternal/fetal genotype incompatibility. Because it is genetic in origin, a maternal/fetal genotype incompatibility is one cause of an adverse environment that can be precisely studied, even years after the adverse environment was present, and thus may provide a useful research approach for identifying prenatal environmental factors that interact with susceptibility genes to cause this disorder. We propose a family-based genetic study to test hypotheses about the role of maternal/fetal genotype incompatibility in schizophrenia.This research integrates the study of genes and environment in an innovative manner and provides the first gene-based test of this highly plausible non-Mendelian mechanism in schizophrenia susceptibility. The research will require the development of some new statistical model specifications -- essential because current research methods are unlikely to detect, or may lead to incorrect inferences about, such an underlying non-Mendelian mechanism. This exploratory study develops the necessary substrate for this area of research using four existing data sets containing more than 2200 individuals with 900 affecteds, comprising at least 300 independent mother, father, affected child trios with diagnoses and DNA, in order to identify promising incompatibilities that would launch a future large-scale data collection effort and detailed hypothesis testing. The study will accomplish: (1) genotyping of plausible incompatibility loci (i.e., HLA, ABO, RHD) in samples with existing genotyping for putative schizophrenia susceptibility loci; (2) development of a maternal/fetal genotype test using new specifications of the gamete competition model and trio comparison model that can decompose incompatibility effects from linkage effects; and, (3) hypothesis testing about, (a) the direct effect of maternal/fetal genotype incompatibility on susceptibility to schizophrenia, (b) the cumulative effect of maternal/fetal genotype incompatibilities, and (c) the interaction of the maternal/fetal genotype incompatibility with a putative schizophrenia susceptibility locus on chromosome lq. This proposal is important because it could lead to a concrete research model in which the essential genetic and environmental elements involved in the etiology of schizophrenia could be studied precisely.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH066001-02
Application #
6642768
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Lehner, Thomas
Project Start
2002-08-02
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$152,500
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Childs, Erica J; Palmer, Christina G S; Lange, Kenneth et al. (2010) Modeling maternal-offspring gene-gene interactions: the extended-MFG test. Genet Epidemiol 34:512-21
Palmer, Christina G S; Mallery, Erin; Turunen, Joni A et al. (2008) Effect of Rhesus D incompatibility on schizophrenia depends on offspring sex. Schizophr Res 104:135-45
Palmer, Christina G S; Hsieh, Hsin-Ju; Reed, Elaine F et al. (2006) HLA-B maternal-fetal genotype matching increases risk of schizophrenia. Am J Hum Genet 79:710-5
Minassian, S L; Palmer, C G S; Turunen, J A et al. (2006) Incorporating serotypes into family based association studies using the MFG test. Ann Hum Genet 70:541-53
Hsieh, Hsin-Ju; Palmer, Christina G S; Harney, Sinead et al. (2006) The v-MFG test: investigating maternal, offspring and maternal-fetal genetic incompatibility effects on disease and viability. Genet Epidemiol 30:333-47
Kraft, Peter; Hsieh, Hsin-ju; Cordell, Heather J et al. (2005) A conditional-on-exchangeable-parental-genotypes likelihood that remains unbiased at the causal locus under multiple-affected-sibling ascertainment. Genet Epidemiol 29:87-90
Minassian, Sonia L; Palmer, Christina G S; Sinsheimer, Janet S (2005) An exact maternal-fetal genotype incompatibility (MFG) test. Genet Epidemiol 28:83-95
Kraft, Peter; Palmer, Christina G S; Woodward, Arthur J et al. (2004) RHD maternal-fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order. Eur J Hum Genet 12:192-8
Sinsheimer, Janet S; Palmer, Christina G S; Woodward, J Arthur (2003) Detecting genotype combinations that increase risk for disease: maternal-fetal genotype incompatibility test. Genet Epidemiol 24:1-13
Palmer, Christina G S; Turunen, Joni A; Sinsheimer, Janet S et al. (2002) RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility. Am J Hum Genet 71:1312-9