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Hum Hered 2011;72:161–172

Detection of Intergenerational Genetic Effects with Application to HLA-B Matching as a Risk Factor for Schizophrenia

Childs E.J.a · Sobel E.M.b · Palmer C.G.S.b, c · Sinsheimer J.S.a, b, d
Departments of aBiostatistics, bHuman Genetics, cPsychiatry and Biobehavioral Sciences, and dBiomathematics, University of California, Los Angeles, Calif., USA
email Corresponding Author

 goto top of outline Key Words

  • Family-based association
  • Maternal-fetal genotype test
  • Extended maternal-fetal genotype test
  • Genotype interactions
  • Complex disease
  • Olfactory deficits
  • Gene-by-gene
  • Gene-by-environment
  • Major histocompatibility complex

 goto top of outline Abstract

Background and Methods: Association studies using unrelated individuals cannot detect intergenerational genetic effects contributing to disease. To detect these effects, we improve the extended maternal-fetal genotype (EMFG) incompatibility test to estimate any combination of maternal effects, offspring effects, and their interactions at polymorphic loci or multiple SNPs, using any size pedigrees. We explore the advantages of using extended pedigrees rather than nuclear families. We apply our methods to schizophrenia pedigrees to investigate whether the previously associated mother-daughter HLA-B matching is a genuine risk or the result of bias. Results: Simulations demonstrate that using the EMFG test with extended pedigrees increases power and precision, while partitioning extended pedigrees into nuclear families can underestimate intergenerational effects. Application to actual data demonstrates that mother-daughter HLA-B matching remains a schizophrenia risk factor. Furthermore, ascertainment and mate selection biases cannot by themselves explain the observed HLA-B matching and schizophrenia association. Conclusions: Our results demonstrate the power of the EMFG test to examine intergenerational genetic effects, highlight the importance of pedigree rather than case/control or case-mother/control-mother designs, illustrate that pedigrees provide a means to examine alternative, non-causal mechanisms, and they strongly support the hypothesis that HLA-B matching is causally involved in the etiology of schizophrenia in females.

Copyright © 2011 S. Karger AG, Basel

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 goto top of outline Author Contacts

Christina Palmer, PhD
UCLA Semel Institute
760 Westwood Plaza, Room 47-422, Los Angeles, CA 90095 (USA)
Tel. +1 310 794 4796, E-Mail
Janet Sinsheimer, PhD
UCLA Gonda Center
695 Charles E. Young Drive South, 5357-C
Los Angeles, CA 90095 (USA)
Tel. +1 310 825 8002, E-Mail

 goto top of outline Article Information

C.G.S. Palmer and J.S. Sinsheimer contributed equally to this work.

Received: June 2, 2011
Accepted after revision: August 23, 2011
Published online: October 15, 2011
Number of Print Pages : 12
Number of Figures : 1, Number of Tables : 5, Number of References : 97

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 72, No. 3, Year 2011 (Cover Date: November 2011)

Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

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