Journal Mobile Options
Table of Contents
Vol. 62, No. 4, 2006
Issue release date: December 2006
Hum Hered 2006;62:175–189
(DOI:10.1159/000096599)

Linkage Disequilibrium and Haplotype Homozygosity in Population Samples Genotyped at a High Marker Density

Wang H.a · Lin C.-H.a · Service S.b · Chen Y.d · Freimer N.b · Sabatti C.a, c
aDepartment of Statistics, bCenter for Neurobehavioral Genetics, and cDepartment of Human Genetics, UCLA, Los Angeles, Calif., and dDepartment of Statistics, University of Illinois at Urbana-Champain, Champain, Ill., USA
email Corresponding Author

Abstract

Objective: Analyze the information contained in homozygous haplotypes detected with high density genotyping. Methods: We analyze the genotypes of ∼2,500 markers on chr 22 in 12 population samples, each including 200 individuals. We develop a measure of disequilibrium based on haplotype homozygosity and an algorithm to identify genomic segments characterized by non-random homozygosity (NRH), taking into account allele frequencies, missing data, genotyping error, and linkage disequilibrium. Results: We show how our measure of linkage disequilibrium based on homozygosity leads to results comparable to those of R2, as well as the importance of correcting for small sample variation when evaluating D′. We observe that the regions that harbor NRH segments tend to be consistent across populations, are gene rich, and are characterized by lower recombination. Conclusions: It is crucial to take into account LD patterns when interpreting long stretches of homozygous markers.


 goto top of outline Key Words

  • Linkage disequilibrium measures
  • Inbreeding
  • Copy number variation
  • Population genetics
  • Genomic loss

 goto top of outline Abstract

Objective: Analyze the information contained in homozygous haplotypes detected with high density genotyping. Methods: We analyze the genotypes of ∼2,500 markers on chr 22 in 12 population samples, each including 200 individuals. We develop a measure of disequilibrium based on haplotype homozygosity and an algorithm to identify genomic segments characterized by non-random homozygosity (NRH), taking into account allele frequencies, missing data, genotyping error, and linkage disequilibrium. Results: We show how our measure of linkage disequilibrium based on homozygosity leads to results comparable to those of R2, as well as the importance of correcting for small sample variation when evaluating D′. We observe that the regions that harbor NRH segments tend to be consistent across populations, are gene rich, and are characterized by lower recombination. Conclusions: It is crucial to take into account LD patterns when interpreting long stretches of homozygous markers.

Copyright © 2006 S. Karger AG, Basel


 goto top of outline References
  1. The International HapMap Consortium: A haplotype map of the human genome. Nature 2005;437:1299–1320.
  2. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG, Frazer KA, Cox DR: Whole-genome patterns of common DNA variation in three human populations. Science 2005;307:1072–1079.
  3. Thomas DC, Haile RW, Duggan D: Recent developments in genomewide association scans: a workshop summary and review. Am J Hum Genet 2005;77:337–345.
  4. Service S, DeYoung J, Karayiorgou M, Louw Roos J, Pretorious H, Bedoya G, Ospina J, Ruiz-Linares A, Macedo A, Palha J, Heutink P, Aulchenko Y, Oostra B, van Duijn C, Jarvelin M, Varilo T, Peddle L, Rahman P, Piras G, Monne M, Murray S, Galver L, Peltonen L, Sabatti C, Collins A, Freimer N: Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nature Genetics 2006;38:556–560.
  5. Sabatti C, Risch N: Homozygosity and linkage disequilibrium. Genetics 2002;160:1707–1719.
  6. Sabatti C: Measuring dependence with volume tests. The American Statistician 2002;50:191–195.

    External Resources

  7. Chen Y, Lin C, Sabatti C: Volume measures for linkage disequilibrium. Submitted, 2006.
  8. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES: Detecting recent positive selection in the human genome from haplotype structure. Nature 2002;419:832–837.
  9. Leutenegger A, Prum B, Genin E, Verny C, Lemainque A, Clerget-Darpoux F, Thompson E: Estimation of the inbreeding coefficient through use of genomic data. Am J Hum Genet 2003;73:516–523.
  10. Newton M, Gould M, Reznikoff C, Haag J: On the statistical analysis of allelic-loss data. Stat Med 2000;17:1425–1445.
  11. Ohta T: Linkage disequilibrium between amino acid sites in immunoglobulin genes and other multigene families. Genet Res 1980;36:181–197.
  12. Hotelling H: Tubes and spheres in n-spaces, and a class of statistical problems. American Journal of Mathematics 1939;61:440–460.

    External Resources

  13. Diaconis P, Efron B: Testing for independence in a two-way table: new interpretations of the Chi-square statistics. The Annals of Statistics 1985;13:845–874.

    External Resources

  14. Woods CG, Cox J, Springell K, Hampshire DJ, Mohamed MD, McKibbin M, Stern R, Raymond FL, Sandford R, Sharif SM, Karbani G, Ahmed M, Bond J, Clayton D, Inglehearn CF: Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am J Hum Genet 2006;78:889–896.
  15. Wang H, Lee Y, Nelson S, Sabatti C: Inferring genomic loss and location of tumor suppressor genes from high density genotypes. Journal of the French Statistical Society 2005;146:153–171.
  16. Iafrate A, Feuk L, Rivera M, Listewnik M, Donahoe P, Qi Y, Scherer SW, Lee C: Detection of large-scale variation in the human genome. Nat Genet 2004;36:949–951.
  17. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam T, Trask B, Patterson N, Zetterberg A, Wigler M: Large-scale copy number polymorphism in the human genome. Science 2004;305:525–528.
  18. Newton M, Lee Y: Inferring the location and effect of tumor suppressor genes by instabilityselection modeling of allelic-loss data. Biometrics 2000;56:1088–1097.
  19. de la Chapelle A, Herva R, Koivisto M, Aula P: A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet 1981;57:253–256.
  20. Scambler PJ, Kelly D, Lindsay E, Williamson R, Goldberg R, Shprintzen R, Wilson DI, Goodship JA, Cross IE, Burn J: Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 1992;339:1138–1139.
  21. Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK, Eisen H, Childs B, Kazazian HH, Kucherlapati R, Antonarakis SE, Pulver AE, Housman DE: Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Nat Acad Sci 1995;92:7612–7616.
  22. Gibson J, Morton N, Collins A: Extended tracts of homozygosity in outbred human populations. Human Molecular Genetics 2006;15:789–795.

 goto top of outline Author Contacts

Chiara Sabatti
Department of Human Genetics, UCLA School of Medicine
695 Charles E. Young Drive South
Los Angeles, CA 90095-7088 (USA)
Tel. +1 310 794 9567, Fax +1 310 794 5446, E-Mail csabatti@mednet.ucla.edu


 goto top of outline Article Information

The international collaborative group on isolated populations members that are not listed separately as authors of this manuscript are: Maria Karayiorgoua, J. Louw Roosb, Herman Pretoriousb, Gabriel Bedoyac, Jorge Ospinad, Andres Ruiz-Linaresc, e, António Macedof, Joana Almeida Palhag, Peter Heutinkh, i, Yurii Aulchenkoj, Ben Oostraj, Cornelia van Duijnj, Marjo-Riitta Jarvelink, l, Teppo Varilom, n, Lynette Peddleo, Proton Rahmanp, Giovanna Pirasq, Maria Monneq, Leena Peltonenm, n, and the affiliations: aRockefeller University, New York, N.Y, USA; bUniversity of Pretoria Weskoppies Hospital, Pretoria, Republic of South Africa; cLaboratorio de Genetica Molecular, Universidad de Antioquia, and dDepartamento de Psiquiatria, Universidad de Antioquia, Medellin, Colombia; eThe Galton Laboratory, Department of Biology (Wolfson House), University College London, London, UK; fInstituto de Psicologia Médica, Faculdade de Medicina, Coimbra, and gLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; hDepartment of Human Genetics, Section of Medical Genomics, VU University Medical Center, and iCenter for Neurogenomics and Cognitive Research, VU University and VU University Medical Center, Amsterdam and jGenetic Epidemiology Unit, Departments of Epidemiology, Biostatistics and Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; kDepartment of Public Health Science and General Practice, University of Oulu, Oulu, Finland; lDepartment of Epidemiology and Public Health, Imperial College London, London, UK; mDepartment of Medical Genetics, University of Helsinki, and nDepartment of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki, Helsinki, Finland; oNewfound Genomics, and pMemorial University of Newfoundland, Newfoundland, Canada; qDivision of Haematology, San Francesco Hospital, Nuoro, Italy.

Received: May 3, 2006
Accepted after revision: August 7, 2006
Published online: October 30, 2006
Number of Print Pages : 15
Number of Figures : 7, Number of Tables : 1, Number of References : 22


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 62, No. 4, Year 2006 (Cover Date: December 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

Objective: Analyze the information contained in homozygous haplotypes detected with high density genotyping. Methods: We analyze the genotypes of ∼2,500 markers on chr 22 in 12 population samples, each including 200 individuals. We develop a measure of disequilibrium based on haplotype homozygosity and an algorithm to identify genomic segments characterized by non-random homozygosity (NRH), taking into account allele frequencies, missing data, genotyping error, and linkage disequilibrium. Results: We show how our measure of linkage disequilibrium based on homozygosity leads to results comparable to those of R2, as well as the importance of correcting for small sample variation when evaluating D′. We observe that the regions that harbor NRH segments tend to be consistent across populations, are gene rich, and are characterized by lower recombination. Conclusions: It is crucial to take into account LD patterns when interpreting long stretches of homozygous markers.



 goto top of outline Author Contacts

Chiara Sabatti
Department of Human Genetics, UCLA School of Medicine
695 Charles E. Young Drive South
Los Angeles, CA 90095-7088 (USA)
Tel. +1 310 794 9567, Fax +1 310 794 5446, E-Mail csabatti@mednet.ucla.edu


 goto top of outline Article Information

The international collaborative group on isolated populations members that are not listed separately as authors of this manuscript are: Maria Karayiorgoua, J. Louw Roosb, Herman Pretoriousb, Gabriel Bedoyac, Jorge Ospinad, Andres Ruiz-Linaresc, e, António Macedof, Joana Almeida Palhag, Peter Heutinkh, i, Yurii Aulchenkoj, Ben Oostraj, Cornelia van Duijnj, Marjo-Riitta Jarvelink, l, Teppo Varilom, n, Lynette Peddleo, Proton Rahmanp, Giovanna Pirasq, Maria Monneq, Leena Peltonenm, n, and the affiliations: aRockefeller University, New York, N.Y, USA; bUniversity of Pretoria Weskoppies Hospital, Pretoria, Republic of South Africa; cLaboratorio de Genetica Molecular, Universidad de Antioquia, and dDepartamento de Psiquiatria, Universidad de Antioquia, Medellin, Colombia; eThe Galton Laboratory, Department of Biology (Wolfson House), University College London, London, UK; fInstituto de Psicologia Médica, Faculdade de Medicina, Coimbra, and gLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; hDepartment of Human Genetics, Section of Medical Genomics, VU University Medical Center, and iCenter for Neurogenomics and Cognitive Research, VU University and VU University Medical Center, Amsterdam and jGenetic Epidemiology Unit, Departments of Epidemiology, Biostatistics and Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; kDepartment of Public Health Science and General Practice, University of Oulu, Oulu, Finland; lDepartment of Epidemiology and Public Health, Imperial College London, London, UK; mDepartment of Medical Genetics, University of Helsinki, and nDepartment of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki, Helsinki, Finland; oNewfound Genomics, and pMemorial University of Newfoundland, Newfoundland, Canada; qDivision of Haematology, San Francesco Hospital, Nuoro, Italy.

Received: May 3, 2006
Accepted after revision: August 7, 2006
Published online: October 30, 2006
Number of Print Pages : 15
Number of Figures : 7, Number of Tables : 1, Number of References : 22


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 62, No. 4, Year 2006 (Cover Date: December 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. The International HapMap Consortium: A haplotype map of the human genome. Nature 2005;437:1299–1320.
  2. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG, Frazer KA, Cox DR: Whole-genome patterns of common DNA variation in three human populations. Science 2005;307:1072–1079.
  3. Thomas DC, Haile RW, Duggan D: Recent developments in genomewide association scans: a workshop summary and review. Am J Hum Genet 2005;77:337–345.
  4. Service S, DeYoung J, Karayiorgou M, Louw Roos J, Pretorious H, Bedoya G, Ospina J, Ruiz-Linares A, Macedo A, Palha J, Heutink P, Aulchenko Y, Oostra B, van Duijn C, Jarvelin M, Varilo T, Peddle L, Rahman P, Piras G, Monne M, Murray S, Galver L, Peltonen L, Sabatti C, Collins A, Freimer N: Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nature Genetics 2006;38:556–560.
  5. Sabatti C, Risch N: Homozygosity and linkage disequilibrium. Genetics 2002;160:1707–1719.
  6. Sabatti C: Measuring dependence with volume tests. The American Statistician 2002;50:191–195.

    External Resources

  7. Chen Y, Lin C, Sabatti C: Volume measures for linkage disequilibrium. Submitted, 2006.
  8. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES: Detecting recent positive selection in the human genome from haplotype structure. Nature 2002;419:832–837.
  9. Leutenegger A, Prum B, Genin E, Verny C, Lemainque A, Clerget-Darpoux F, Thompson E: Estimation of the inbreeding coefficient through use of genomic data. Am J Hum Genet 2003;73:516–523.
  10. Newton M, Gould M, Reznikoff C, Haag J: On the statistical analysis of allelic-loss data. Stat Med 2000;17:1425–1445.
  11. Ohta T: Linkage disequilibrium between amino acid sites in immunoglobulin genes and other multigene families. Genet Res 1980;36:181–197.
  12. Hotelling H: Tubes and spheres in n-spaces, and a class of statistical problems. American Journal of Mathematics 1939;61:440–460.

    External Resources

  13. Diaconis P, Efron B: Testing for independence in a two-way table: new interpretations of the Chi-square statistics. The Annals of Statistics 1985;13:845–874.

    External Resources

  14. Woods CG, Cox J, Springell K, Hampshire DJ, Mohamed MD, McKibbin M, Stern R, Raymond FL, Sandford R, Sharif SM, Karbani G, Ahmed M, Bond J, Clayton D, Inglehearn CF: Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am J Hum Genet 2006;78:889–896.
  15. Wang H, Lee Y, Nelson S, Sabatti C: Inferring genomic loss and location of tumor suppressor genes from high density genotypes. Journal of the French Statistical Society 2005;146:153–171.
  16. Iafrate A, Feuk L, Rivera M, Listewnik M, Donahoe P, Qi Y, Scherer SW, Lee C: Detection of large-scale variation in the human genome. Nat Genet 2004;36:949–951.
  17. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam T, Trask B, Patterson N, Zetterberg A, Wigler M: Large-scale copy number polymorphism in the human genome. Science 2004;305:525–528.
  18. Newton M, Lee Y: Inferring the location and effect of tumor suppressor genes by instabilityselection modeling of allelic-loss data. Biometrics 2000;56:1088–1097.
  19. de la Chapelle A, Herva R, Koivisto M, Aula P: A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet 1981;57:253–256.
  20. Scambler PJ, Kelly D, Lindsay E, Williamson R, Goldberg R, Shprintzen R, Wilson DI, Goodship JA, Cross IE, Burn J: Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 1992;339:1138–1139.
  21. Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK, Eisen H, Childs B, Kazazian HH, Kucherlapati R, Antonarakis SE, Pulver AE, Housman DE: Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Nat Acad Sci 1995;92:7612–7616.
  22. Gibson J, Morton N, Collins A: Extended tracts of homozygosity in outbred human populations. Human Molecular Genetics 2006;15:789–795.