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Table of Contents
Vol. 67, No. 2, 2009
Issue release date: January 2009
Free Access
Hum Hered 2009;67:104–115
(DOI:10.1159/000179558)

Deviations from Hardy-Weinberg Equilibrium in Parental and Unaffected Sibling Genotype Data

Li B. · Leal S.M.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex., USA
email Corresponding Author

Abstract

Background: Genotyping error can increase both type I and II errors. In order to elucidate potential genotyping errors, data quality control often includes testing genotype data for deviations from Hardy-Weinberg Equilibrium (HWE). Methods: The Hardy-Weinberg Disequilibrium (HWD) coefficient and the ability to reject the null hypothesis of HWE were calculated analytically for genotype data from parents and unaffected siblings of affected probands. Results: Genotype data from parents and unaffected siblings display deviations from HWE when functional or markers in LD with functional locus are tested. For the parental genotype data all deviations from HWE are negative, indicating an excess of heterozygous genotypes with the strongest deviations from HWE observed for the multiplicative model. In contrast, for affected proband genotype data, there is no deviation from HWE under the multiplicative model and the deviations from HWE for the recessive model are positive. For the unaffected sibling data, patterns of deviation from HWE are similar to those observed in the proband data with the exception of the multiplicative model where the HWD coefficient although close to 0 can be either positive or negative depending on the allele frequency. Conclusion: Deviations from HWE in parental and unaffected sibling genotype data could be due to an association with the functional locus. However these deviations for genotypic relative risk ≤2.0 are not large and therefore the power to detect them is usually low. Testing for deviations from HWE in parental and unaffected sibling genotype data is still beneficial for quality control even though functional loci, in parental and unaffected sibling genotype data, can produce an association signal.


 goto top of outline Key Words

  • Association studies
  • Data quality control
  • Family and population based data
  • Hardy-Weinberg Equilibrium

 goto top of outline Abstract

Background: Genotyping error can increase both type I and II errors. In order to elucidate potential genotyping errors, data quality control often includes testing genotype data for deviations from Hardy-Weinberg Equilibrium (HWE). Methods: The Hardy-Weinberg Disequilibrium (HWD) coefficient and the ability to reject the null hypothesis of HWE were calculated analytically for genotype data from parents and unaffected siblings of affected probands. Results: Genotype data from parents and unaffected siblings display deviations from HWE when functional or markers in LD with functional locus are tested. For the parental genotype data all deviations from HWE are negative, indicating an excess of heterozygous genotypes with the strongest deviations from HWE observed for the multiplicative model. In contrast, for affected proband genotype data, there is no deviation from HWE under the multiplicative model and the deviations from HWE for the recessive model are positive. For the unaffected sibling data, patterns of deviation from HWE are similar to those observed in the proband data with the exception of the multiplicative model where the HWD coefficient although close to 0 can be either positive or negative depending on the allele frequency. Conclusion: Deviations from HWE in parental and unaffected sibling genotype data could be due to an association with the functional locus. However these deviations for genotypic relative risk ≤2.0 are not large and therefore the power to detect them is usually low. Testing for deviations from HWE in parental and unaffected sibling genotype data is still beneficial for quality control even though functional loci, in parental and unaffected sibling genotype data, can produce an association signal.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. Boss I: Misclassification in 2 × 2 tables. Biometrics 1954;10:487.

    External Resources

  2. Gordon D, Finch SJ, Nothnagel M, Ott J: Power and sample size calculations for case-control genetic association tests when errors are present: Application to single nucleotide polymorphisms. Hum Hered 2002;54:22–33.
  3. Gordon D, Heath SC, Liu X, Ott J: A transmission/disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data. Am J Hum Genet 2001;69:371–380.
  4. Gordon D, Levenstien MA, Finch SJ, Ott J: Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case-control association studies. Pac Symp Biocomput 2003:490–501.

    External Resources

  5. Gordon D, Heath SC, Ott J: True pedigree errors more frequent than apparent errors for single nucleotide polymorphisms. Hum Hered 1999;49:65–70.
  6. Douglas JA, Skol AD, Boehnke M: Probability of detection of genotyping errors and mutations as inheritance inconsistencies in nuclear-family data. Am J Hum Genet 2002;70:487–495.
  7. Geller F, Ziegler A: Detection rates for genotyping errors in snps using the trio design. Hum Hered 2002;54:111–117.
  8. Douglas JA, Boehnke M, Lange K: A multipoint method for detecting genotyping errors and mutations in sibling-pair linkage data. Am J Hum Genet 2000;66:1287–1297.
  9. Gordon D, Leal SM, Heath SC, Ott J: An analytic solution to single nucleotide polymorphism error-detection rates in nuclear families: Implications for study design. Pac Symp Biocomput 2000:663–674.

    External Resources

  10. Brzustowicz LM, Merette C, Xie X, Townsend L, Gilliam TC, Ott J: Molecular and statistical approaches to the detection and correction of errors in genotype databases. Am J Hum Genet 1993;53:1137–1145.
  11. Ehm MG, Kimmel M, Cottingham RW Jr: Error detection for genetic data, using likelihood methods. Am J Hum Genet 1996;58:225–234.
  12. Lincoln SE, Lander ES: Systematic detection of errors in genetic linkage data. Genomics 1992;14:604–610.
  13. Stringham HM, Boehnke M: Identifying marker typing incompatibilities in linkage analysis. Am J Hum Genet 1996;59:946–950.
  14. Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, Riley J, Purvis I, Xu CF: Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur J Hum Genet 2004;12:395–399.
  15. Tiret L, Cambien F: Departure from Hardy-Weinberg equilibrium should be systematically tested in studies of association between genetic markers and disease. Circulation 1995;92:3364–3365.
  16. Xu J, Turner A, Little J, Bleecker ER, Meyers DA: Positive results in association studies are associated with departure from Hardy-Weinberg equilibrium: Hint for genotyping error? Hum Genet 2002;111:573–574.
  17. Leal SM: Detection of genotyping errors and pseudo-snps via deviations from Hardy-Weinberg equilibrium. Genet Epidemiol 2005;29:204–214.
  18. Cockerham CC: Group inbreeding and coancestry. Genetics 1967;56:89–104.
  19. Cockerham CC: Variance of gene frequencies. Evolution 1969;23:72–78.

    External Resources

  20. Crow JK, M: An Introduction to Population Genetics Theory. Harper and Row, New York 1970.
  21. Deng HW, Chen WM, Recker RR: Population admixture: Detection by Hardy-Weinberg test and its quantitative effects on linkage-disequilibrium methods for localizing genes underlying complex traits. Genetics 2001;157:885–897.
  22. Weir BS, Hill WG, Cardon LR: Allelic association patterns for a dense snp map. Genet Epidemiol 2004;27:442–450.
  23. Dudbridge F, Gusnanto A: Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 2008, in press.
  24. Agresti A: Categorical Data Analysis. John Wiley & Sons, Hoboken, New Jersey 2002.
  25. Nielsen DM, Ehm MG, Weir BS: Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998;63:1531–1540.
  26. Wittke-Thompson JK, Pluzhnikov A, Cox NJ: Rational inferences about departures from Hardy-Weinberg equilibrium. Am J Hum Genet 2005;76:967–986.

 goto top of outline Author Contacts

Dr. Suzanne M. Leal
Baylor College of Medicine, Department of Molecular and Human Genetics
One Baylor Plaza N1619.01
Houston, TX 77030 (USA)
Tel. +1 713 798 4011, Fax +1 713 798 4373, E-Mail sleal@bcm.edu


 goto top of outline Article Information

Received: December 11, 2008
Accepted after revision: April 24, 2008
Published online: December 12, 2008
Number of Print Pages : 12
Number of Figures : 3, Number of Tables : 1, Number of References : 26
Additional supplementary material is available online - Number of Parts : 2


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 67, No. 2, Year 2009 (Cover Date: January 2009)

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

Background: Genotyping error can increase both type I and II errors. In order to elucidate potential genotyping errors, data quality control often includes testing genotype data for deviations from Hardy-Weinberg Equilibrium (HWE). Methods: The Hardy-Weinberg Disequilibrium (HWD) coefficient and the ability to reject the null hypothesis of HWE were calculated analytically for genotype data from parents and unaffected siblings of affected probands. Results: Genotype data from parents and unaffected siblings display deviations from HWE when functional or markers in LD with functional locus are tested. For the parental genotype data all deviations from HWE are negative, indicating an excess of heterozygous genotypes with the strongest deviations from HWE observed for the multiplicative model. In contrast, for affected proband genotype data, there is no deviation from HWE under the multiplicative model and the deviations from HWE for the recessive model are positive. For the unaffected sibling data, patterns of deviation from HWE are similar to those observed in the proband data with the exception of the multiplicative model where the HWD coefficient although close to 0 can be either positive or negative depending on the allele frequency. Conclusion: Deviations from HWE in parental and unaffected sibling genotype data could be due to an association with the functional locus. However these deviations for genotypic relative risk ≤2.0 are not large and therefore the power to detect them is usually low. Testing for deviations from HWE in parental and unaffected sibling genotype data is still beneficial for quality control even though functional loci, in parental and unaffected sibling genotype data, can produce an association signal.



 goto top of outline Author Contacts

Dr. Suzanne M. Leal
Baylor College of Medicine, Department of Molecular and Human Genetics
One Baylor Plaza N1619.01
Houston, TX 77030 (USA)
Tel. +1 713 798 4011, Fax +1 713 798 4373, E-Mail sleal@bcm.edu


 goto top of outline Article Information

Received: December 11, 2008
Accepted after revision: April 24, 2008
Published online: December 12, 2008
Number of Print Pages : 12
Number of Figures : 3, Number of Tables : 1, Number of References : 26
Additional supplementary material is available online - Number of Parts : 2


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 67, No. 2, Year 2009 (Cover Date: January 2009)

Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 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. Boss I: Misclassification in 2 × 2 tables. Biometrics 1954;10:487.

    External Resources

  2. Gordon D, Finch SJ, Nothnagel M, Ott J: Power and sample size calculations for case-control genetic association tests when errors are present: Application to single nucleotide polymorphisms. Hum Hered 2002;54:22–33.
  3. Gordon D, Heath SC, Liu X, Ott J: A transmission/disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data. Am J Hum Genet 2001;69:371–380.
  4. Gordon D, Levenstien MA, Finch SJ, Ott J: Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case-control association studies. Pac Symp Biocomput 2003:490–501.

    External Resources

  5. Gordon D, Heath SC, Ott J: True pedigree errors more frequent than apparent errors for single nucleotide polymorphisms. Hum Hered 1999;49:65–70.
  6. Douglas JA, Skol AD, Boehnke M: Probability of detection of genotyping errors and mutations as inheritance inconsistencies in nuclear-family data. Am J Hum Genet 2002;70:487–495.
  7. Geller F, Ziegler A: Detection rates for genotyping errors in snps using the trio design. Hum Hered 2002;54:111–117.
  8. Douglas JA, Boehnke M, Lange K: A multipoint method for detecting genotyping errors and mutations in sibling-pair linkage data. Am J Hum Genet 2000;66:1287–1297.
  9. Gordon D, Leal SM, Heath SC, Ott J: An analytic solution to single nucleotide polymorphism error-detection rates in nuclear families: Implications for study design. Pac Symp Biocomput 2000:663–674.

    External Resources

  10. Brzustowicz LM, Merette C, Xie X, Townsend L, Gilliam TC, Ott J: Molecular and statistical approaches to the detection and correction of errors in genotype databases. Am J Hum Genet 1993;53:1137–1145.
  11. Ehm MG, Kimmel M, Cottingham RW Jr: Error detection for genetic data, using likelihood methods. Am J Hum Genet 1996;58:225–234.
  12. Lincoln SE, Lander ES: Systematic detection of errors in genetic linkage data. Genomics 1992;14:604–610.
  13. Stringham HM, Boehnke M: Identifying marker typing incompatibilities in linkage analysis. Am J Hum Genet 1996;59:946–950.
  14. Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, Riley J, Purvis I, Xu CF: Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur J Hum Genet 2004;12:395–399.
  15. Tiret L, Cambien F: Departure from Hardy-Weinberg equilibrium should be systematically tested in studies of association between genetic markers and disease. Circulation 1995;92:3364–3365.
  16. Xu J, Turner A, Little J, Bleecker ER, Meyers DA: Positive results in association studies are associated with departure from Hardy-Weinberg equilibrium: Hint for genotyping error? Hum Genet 2002;111:573–574.
  17. Leal SM: Detection of genotyping errors and pseudo-snps via deviations from Hardy-Weinberg equilibrium. Genet Epidemiol 2005;29:204–214.
  18. Cockerham CC: Group inbreeding and coancestry. Genetics 1967;56:89–104.
  19. Cockerham CC: Variance of gene frequencies. Evolution 1969;23:72–78.

    External Resources

  20. Crow JK, M: An Introduction to Population Genetics Theory. Harper and Row, New York 1970.
  21. Deng HW, Chen WM, Recker RR: Population admixture: Detection by Hardy-Weinberg test and its quantitative effects on linkage-disequilibrium methods for localizing genes underlying complex traits. Genetics 2001;157:885–897.
  22. Weir BS, Hill WG, Cardon LR: Allelic association patterns for a dense snp map. Genet Epidemiol 2004;27:442–450.
  23. Dudbridge F, Gusnanto A: Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 2008, in press.
  24. Agresti A: Categorical Data Analysis. John Wiley & Sons, Hoboken, New Jersey 2002.
  25. Nielsen DM, Ehm MG, Weir BS: Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998;63:1531–1540.
  26. Wittke-Thompson JK, Pluzhnikov A, Cox NJ: Rational inferences about departures from Hardy-Weinberg equilibrium. Am J Hum Genet 2005;76:967–986.