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Table of Contents
Vol. 62, No. 3, 2006
Issue release date: November 2006
Hum Hered 2006;62:165–174
(DOI:10.1159/000096444)

Allowing for Missing Data at Highly Polymorphic Genes when Testing for Maternal, Offspring and Maternal-Fetal Genotype Incompatibility Effects

Hsieh H.-J.a1 · Palmer C.G.S.b, c · Sinsheimer J.S.a, c, d
aBiostatistics, bDepartment of Psychiatry and Biobehavioral Sciences, cHuman Genetics, dBiomathematics, University of California, Los Angeles, Calif., USA
email Corresponding Author

Abstract

Genes can be associated with disease through an individual’s inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene’s functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring’s genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test’s performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.


 goto top of outline Key Words

  • Family-based study
  • Association
  • Identity-by-state
  • Missing data
  • Maternal-fetal genotype incompatibility

 goto top of outline Abstract

Genes can be associated with disease through an individual’s inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene’s functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring’s genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test’s performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.

Copyright © 2006 S. Karger AG, Basel


 goto top of outline References
  1. Dyment DA, Ebers GC, Sadovnick AD: Genetics of multiple sclerosis. Lancet Neurol 2004;3:104–110.
  2. Dyment DA, Herrera BM, Cader MZ, Willer CJ, Lincoln MR, Sadovnick AD, Risch N, Ebers GC: Complex interactions among MHC haplotypes in multiple sclerosis. Hum Mol Genet 2005;14:2019–2026.
  3. Sinsheimer JS, Palmer CGS, Woodward JA: Detecting genotype combinations that increase risk for disease: The maternal-fetal genotype incompatibility test. Genetic Epidemiology 2003;24:1–13.
  4. Stubbs EG, Ritvo ER, Mason-Brothers A: Autism and shared parental HLA antigens. J Am Acad Child Psychiatry 1985;24:182–185.
  5. Palmer CSG, Hsieh H-J, Reed EF, Lonnqvist J, Peltonen L, Woodward JA, Sinsheimer JS: HLA-B maternal-fetal genotype matching increases risk of schizophrenia. Am J Hum Genet 2006;79:710–715.
  6. Stevens AM, Tsao BP, Hahn BH, Guthrie K, Lambert NC, Porter AJ, Tylee TS, Nelson JL: Maternal HLA class II compatibility in men with systemic lupus erythematosus. Arthritis Rheum 2005;52:2768–2773.
  7. Willer CJ, Dyment DA, Sadovnick AD, Ebers GC: Maternal–offspring HLA-DRB1 compatibility in multiple sclerosis. Tissue Antigens 2005;66:44–47.
  8. Curtis D, Sham PC: A note on the application of the transmission disequilibrium test when a parent is missing. Am J Hum Genet 1995;56:811–812.
  9. Clayton D: A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999;65:1170–1177.
  10. Rabinowitz D, Laird N: A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000;50:211–223.
  11. Rabinowitz D: Adjusting for population heterogeneity and misspecified haplotype frequencies when testing nonparametric null hypotheses in statistical genetics. Journal of the American Statistical Association 2002;97:742–758.

    External Resources

  12. Chen YH: New approach to association testing in case-parent designs under informative parental missingness. Genet Epidemiol 2004;27:131–140.
  13. Palmer CGS, Turunen JA, Sinsheimer JS, Minassian M, Paunio T, Lonnqvist J, Peltonen L, Woodward JA: RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility. American Journal of Human Genetics 2002;71:1312–1319.
  14. Schaid DJ: Adjusting for population heterogeneity and misspecified haplotype frequencies when testing nonparametric null hypotheses in statistical genetics – Comment. Journal of the American Statistical Association 2002;97:754–756.

    External Resources

  15. Weinberg CR: Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet 1999;64:1186–1193.
  16. Minassian SL, Palmer CGS, Turunen JA, Paunio T, Lonnqvist J, Peltonen L, Woodward AJ, Sinsheimer JS: Incorporating serotypes into family based association studies using the MFG test. Annals of Human Genetics 2006, in press.
  17. Lange K: SEARCH. Department of Biomathematics, University of California, Los Angeles: Los Angeles, 1991.
  18. Beydoun H, Saftlas AF: Association of human leukocyte antigen sharing with recurrent spontaneous abortions. Tissue Antigens 2005;65:123–135.
  19. Ober C, Hyslop T, Elias S, Weitkamp LR, Hauck W: Human leukocyte antigen matching and fetal loss: Results of a 10 year prospective study. Human Reproduction 1998;13:33–38.
  20. Kraft P, Palmer CGS, Woodward JA, Turunen JA, Minassian M, Paunio T, Lonnqvist J, Peltonen L, Sinsheimer JS: RHD Maternal-Fetal genotype incompatibility and schizophrenia: Extending the MFG test to include multiple siblings and birth order. European Journal of Human Genetics 2004;12:192–198.
  21. Hsieh H, Palmer CGS, Harney S, Newton JL, Wordsworth P, Brown MA, Sinsheimer JS: The v-MFG test: Investigating maternal, offspring, and maternal-fetal genetic incompatibilities effects on disease and viability. Genet Epidemiol 2006;30:333–347.
  22. Little RJA, Rubin D, Statistical analysis with missing data. 2nd ed. 2002, Hoboken: Wiley-Interscience.
  23. Ferguson TS: A Course in Large Sample Theory. 1996:Chapman & Hall/CRC.
  24. Kraft P, Hsieh HJ, Cordell HJ, Sinsheimer J: A conditional-on-exchangeable-parental-genotypes likelihood that remains unbiased at the causal locus under multiple-affected-sibling ascertainment. Genet Epidemiol 2005;29:87–90.
  25. Allen A, Rathouz P, Satten GA: Informative missingness in genetic association studies: Case-parent designs. American Journal of Human Genetics 2003;72:671–680.
  26. Clayton D, Chapman J, Cooper J: Use of unphased multilocus genotype data in indirect association studies. Genet Epidemiol 2004;27:415–428.
  27. Li W, Gregersen PK: Reconstructing Haplotypes in Pedigrees: Importance of Parental Information. American Journal of Medical Genetics 2004;124A:107–109.

    External Resources

  28. Kuhn L, Abrams EJ, Palumbo P, Bulterys M, Aga R, Louie L, Hodge T: Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression. Aids 2004;18:1281–1289.

 goto top of outline Author Contacts

Dr. Janet Sinsheimer
Department of Human Genetics, 5357C Gonda Center
695 Charles E. Young Drive South, Box 957088
Los Angeles, CA 90095-7088 (USA)
Tel. +1 310 825 8002, Fax +1 310 825 8685, E-Mail janet@mednet.ucla.edu


 goto top of outline Article Information

Received: April 3, 2006
Accepted after revision: August 7, 2006
Published online: October 25, 2006
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 3, Number of References : 28


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 62, No. 3, Year 2006 (Cover Date: November 2006)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Genes can be associated with disease through an individual’s inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene’s functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring’s genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test’s performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.



 goto top of outline Author Contacts

Dr. Janet Sinsheimer
Department of Human Genetics, 5357C Gonda Center
695 Charles E. Young Drive South, Box 957088
Los Angeles, CA 90095-7088 (USA)
Tel. +1 310 825 8002, Fax +1 310 825 8685, E-Mail janet@mednet.ucla.edu


 goto top of outline Article Information

Received: April 3, 2006
Accepted after revision: August 7, 2006
Published online: October 25, 2006
Number of Print Pages : 10
Number of Figures : 2, Number of Tables : 3, Number of References : 28


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 62, No. 3, Year 2006 (Cover Date: November 2006)

Journal Editor: Devoto, M. (Philadelphia, Pa.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Dyment DA, Ebers GC, Sadovnick AD: Genetics of multiple sclerosis. Lancet Neurol 2004;3:104–110.
  2. Dyment DA, Herrera BM, Cader MZ, Willer CJ, Lincoln MR, Sadovnick AD, Risch N, Ebers GC: Complex interactions among MHC haplotypes in multiple sclerosis. Hum Mol Genet 2005;14:2019–2026.
  3. Sinsheimer JS, Palmer CGS, Woodward JA: Detecting genotype combinations that increase risk for disease: The maternal-fetal genotype incompatibility test. Genetic Epidemiology 2003;24:1–13.
  4. Stubbs EG, Ritvo ER, Mason-Brothers A: Autism and shared parental HLA antigens. J Am Acad Child Psychiatry 1985;24:182–185.
  5. Palmer CSG, Hsieh H-J, Reed EF, Lonnqvist J, Peltonen L, Woodward JA, Sinsheimer JS: HLA-B maternal-fetal genotype matching increases risk of schizophrenia. Am J Hum Genet 2006;79:710–715.
  6. Stevens AM, Tsao BP, Hahn BH, Guthrie K, Lambert NC, Porter AJ, Tylee TS, Nelson JL: Maternal HLA class II compatibility in men with systemic lupus erythematosus. Arthritis Rheum 2005;52:2768–2773.
  7. Willer CJ, Dyment DA, Sadovnick AD, Ebers GC: Maternal–offspring HLA-DRB1 compatibility in multiple sclerosis. Tissue Antigens 2005;66:44–47.
  8. Curtis D, Sham PC: A note on the application of the transmission disequilibrium test when a parent is missing. Am J Hum Genet 1995;56:811–812.
  9. Clayton D: A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999;65:1170–1177.
  10. Rabinowitz D, Laird N: A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000;50:211–223.
  11. Rabinowitz D: Adjusting for population heterogeneity and misspecified haplotype frequencies when testing nonparametric null hypotheses in statistical genetics. Journal of the American Statistical Association 2002;97:742–758.

    External Resources

  12. Chen YH: New approach to association testing in case-parent designs under informative parental missingness. Genet Epidemiol 2004;27:131–140.
  13. Palmer CGS, Turunen JA, Sinsheimer JS, Minassian M, Paunio T, Lonnqvist J, Peltonen L, Woodward JA: RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility. American Journal of Human Genetics 2002;71:1312–1319.
  14. Schaid DJ: Adjusting for population heterogeneity and misspecified haplotype frequencies when testing nonparametric null hypotheses in statistical genetics – Comment. Journal of the American Statistical Association 2002;97:754–756.

    External Resources

  15. Weinberg CR: Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet 1999;64:1186–1193.
  16. Minassian SL, Palmer CGS, Turunen JA, Paunio T, Lonnqvist J, Peltonen L, Woodward AJ, Sinsheimer JS: Incorporating serotypes into family based association studies using the MFG test. Annals of Human Genetics 2006, in press.
  17. Lange K: SEARCH. Department of Biomathematics, University of California, Los Angeles: Los Angeles, 1991.
  18. Beydoun H, Saftlas AF: Association of human leukocyte antigen sharing with recurrent spontaneous abortions. Tissue Antigens 2005;65:123–135.
  19. Ober C, Hyslop T, Elias S, Weitkamp LR, Hauck W: Human leukocyte antigen matching and fetal loss: Results of a 10 year prospective study. Human Reproduction 1998;13:33–38.
  20. Kraft P, Palmer CGS, Woodward JA, Turunen JA, Minassian M, Paunio T, Lonnqvist J, Peltonen L, Sinsheimer JS: RHD Maternal-Fetal genotype incompatibility and schizophrenia: Extending the MFG test to include multiple siblings and birth order. European Journal of Human Genetics 2004;12:192–198.
  21. Hsieh H, Palmer CGS, Harney S, Newton JL, Wordsworth P, Brown MA, Sinsheimer JS: The v-MFG test: Investigating maternal, offspring, and maternal-fetal genetic incompatibilities effects on disease and viability. Genet Epidemiol 2006;30:333–347.
  22. Little RJA, Rubin D, Statistical analysis with missing data. 2nd ed. 2002, Hoboken: Wiley-Interscience.
  23. Ferguson TS: A Course in Large Sample Theory. 1996:Chapman & Hall/CRC.
  24. Kraft P, Hsieh HJ, Cordell HJ, Sinsheimer J: A conditional-on-exchangeable-parental-genotypes likelihood that remains unbiased at the causal locus under multiple-affected-sibling ascertainment. Genet Epidemiol 2005;29:87–90.
  25. Allen A, Rathouz P, Satten GA: Informative missingness in genetic association studies: Case-parent designs. American Journal of Human Genetics 2003;72:671–680.
  26. Clayton D, Chapman J, Cooper J: Use of unphased multilocus genotype data in indirect association studies. Genet Epidemiol 2004;27:415–428.
  27. Li W, Gregersen PK: Reconstructing Haplotypes in Pedigrees: Importance of Parental Information. American Journal of Medical Genetics 2004;124A:107–109.

    External Resources

  28. Kuhn L, Abrams EJ, Palumbo P, Bulterys M, Aga R, Louie L, Hodge T: Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression. Aids 2004;18:1281–1289.