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Vol. 58, No. 1, 2004
Issue release date: December 2004
Hum Hered 2004;58:2–9
(DOI:10.1159/000081451)

Mapping Genes for Common Diseases: The Case for Genetic (LD) Maps

Collins A.a · Lau W.a · De La Vega F.M.b
aHuman Genetics, School of Medicine, University of Southampton, Southampton, UK; bApplied Biosystems, Foster City, Calif., USA
email Corresponding Author

Abstract

We examine the current effort to develop a haplotype map of the human genome and suggest an alternative approach which represents linkage disequilibrium patterns in the form of a metric LD map. LD maps have some of the useful properties of genetic linkage maps but have a much higher resolution which is optimal for SNP-based association mapping of common diseases. The studies that have been undertaken to date suggest that LD and recombination maps show some close similarities because of abundant, narrow, recombination hot spots. These hot spots are co-localised in all populations but, unlike linkage maps, LD maps differ in scale for different populations because of differences in population history. The prospects for developing optimized panels of SNPs and the use of linkage disequilibrium maps in disease gene localisation are assessed in the light of recent evidence.


 goto top of outline Key Words

  • Linkage disequilibrium map
  • Linkage map
  • Haplotype block
  • HapMap project
  • Recombination hot spot

 goto top of outline Abstract

We examine the current effort to develop a haplotype map of the human genome and suggest an alternative approach which represents linkage disequilibrium patterns in the form of a metric LD map. LD maps have some of the useful properties of genetic linkage maps but have a much higher resolution which is optimal for SNP-based association mapping of common diseases. The studies that have been undertaken to date suggest that LD and recombination maps show some close similarities because of abundant, narrow, recombination hot spots. These hot spots are co-localised in all populations but, unlike linkage maps, LD maps differ in scale for different populations because of differences in population history. The prospects for developing optimized panels of SNPs and the use of linkage disequilibrium maps in disease gene localisation are assessed in the light of recent evidence.

Copyright © 2004 S. Karger AG, Basel


 goto top of outline References
  1. Lonjou C, Collins A, Ajioka RS, Jorde LB, Kushner JP, Morton NE: Allelic association under map error and recombinational heterogeneity: A tale of two sites. Proc Natl Acad Sci USA 1998;95:11366–11370.
  2. Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 1996;273:1516–1517.
  3. Van Eerdewegh P, et al: Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002;418:426–439.
  4. Altshuler D, et al: The common PPAR gamma Pro12A1a polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000;26:76–80.
  5. Stefansson H, et al: Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002;71:877–892.
  6. Rioux JD, et al: Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001;29:223–228.
  7. Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG: Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 2001;357:1925–1928.
  8. Pritchard JK: Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001;69:124–137.
  9. Lander ES: The new genomics: global views of biology. Science 1996;274:536–539.
  10. Kruglyak L: Genetic isolates: Separate but equal? Proc Natl Acad Sci USA 1999;96:1170–1172.
  11. Kruglyak L: Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999;22:139–144.
  12. Lonjou C, Collins A, Morton NE: Allelic association between marker loci. Proc Natl Acad Sci USA 1999;96:1621–1626.
  13. Collins A, Lonjou C, Morton NE: Genetic epidemiology of single nucleotide polymorphisms. Proc Natl Acad Sci USA 1999;96:15173–15177.
  14. Service SK, Ophoff RA, Freimer NB: The genome-wide distribution of background linkage disequilibrium in a population isolate. Hum Mol Genet 2001;10:545–551
  15. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES: Linkage disequilibrium in the human genome. Nature 2001;411:199–204.
  16. De La Vega FM, Avi-Itzhak H, Halldorsson B, Scafe C, Istrail S, Gilbert DA, Spier EG: Distribution, sharing, and ancestry of common haplotypes in African-American, Caucasian and Asian populations. Am J Hum Genet 2003;73(5):267.
  17. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES: High-resolution haplotype structure in the human genome. Nat Genet 2001;29:229–232.
  18. The International HapMap Consortium: The International HapMap project. Nature 2003;426:789–796.
  19. Johnson GCL, et al: Haplotype tagging for the identification of common disease genes. Nature Genet 2001;29:233–237.
  20. Gabriel SB, et al: The structure of haplotype blocks in the human genome. Science 2002;296:2225–2229.
  21. Botstein D, Risch N: Discovering genotypes underlying human phenotypes: Past successes for mendelian disease, future approaches for complex disease. Nat Genet Suppl 2003;33:228–237.
  22. Patil N, et al: Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 2001;294:1719–1723.
  23. Zhang K, et al: A dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci USA 2002;99:7335–7339.
  24. Mannila H, Koivisto M, Perola M, Varilo T, Hennah W, Ekelund J, Lukk M, Peltonen L, Ukkonen E: Minimum description length block finder, a method to identify haplotype blocks and to compare the strength of block boundaries. Am J Hum Genet 2003;73:86–94.
  25. Phillips MS, Lawrence R, Sachidanandam R, Morris AP, Balding DJ, Donaldson MA, Studebaker JF, Ankener WM, Alfisi SV, Kuo FS, et al: Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots. Nat Genet 2003;33:382–387.
  26. Ke X, Hunt S, Tapper W, Lawrence R, Stavrides G, Ghori J, Whittaker P, Collins A, Morris AP, Bentley D, Cardon LR, Deloukas P: The impact of SNP density on fine-scale patterns of linkage disequilibrium. Hum Mol Genet 2004;13:577–588.
  27. Wang N, Akey JM, Zhang K, Chakraborty R, Jin L: Distribution of recombination crossovers and the origin of haplotype blocks: The interplay of population history, recombination and mutation. Am J Hum Genet 2002;71:1227–1234.
  28. Wall JD, Pritchard JK: Haplotype blocks and linkage disequiulibrium in the human genome. Nat Rev Genet 2003;4:587–597.
  29. Kauppi L, Sajantila A, Jeffreys AJ: Recombination hotspots rather than population history dominate linkage disequilibrium in the MHC class II region. Hum Mol Genet 2003;12:33–40.
  30. Oota H, Pakstis AJ, Bonne-Tamir B, Goldman D, Grigorenko E, Kajuna SL, Karoma NJ, Kungulilo S, Lu RB, Odunsi K, Okonofua F, Zhukova OV, Kidd JR, Kidd KK: The evolution and population genetics of the ALDH2 locus: random genetic drift, selection, and low levels of recombination. Ann Hum Genet 2004;68:93–109.
  31. Morton NE, Zhang W, Taillon-Miller P, Ennis S, Kwok P-Y, Collins A: The optimal measure of allelic association. Proc Natl Acad Sci USA 2001;98:5217–5222.
  32. Malecot G: The Mathematics of Heredity. San Francisco, Freeman, 1969.
  33. Collins A, Morton NE: Mapping a disease locus by allelic association. Proc Natl Acad Sci USA 1998;95:1741–1745.
  34. Shete S: A note on the optimal measure of allelic association. Ann Hum Genet 2003;67:189–191.
  35. Devlin B, Risch N: A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 1995;29:311–322.
  36. Jeffreys AJ, Kauppi L, Neumann R: Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex, Nat Genet 2001;29:217–222.
  37. Maniatis N, Collins A, Ku X-F, McCarthy LC, Hewett DR, Tapper W, Ennis S, Ke X, Morton NE: The first linkage disequilibrium (LD) maps: Delineation of hot and cold blocks by diplotype analysis. Proc Natl Acad Sci USA 2002;99:2228–2233.
  38. Tapper WJ, Morton NE, Dunham I, Ke X, Collins A: A sequence-based map of chromosome 22. Genome Res 2001;11:1290–1295.
  39. Dawson E, et al: A first-generation linkage disequilibrium map of human chromosome 22. Nature 2002;418:544–548.
  40. Kong, et al: A high-resolution recombination map of the human genome. Nature Genet 2002;31:241–247.
  41. Li N, Stephens M: Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 2003;165:2213–2233.
  42. McVean GAT, Myers SR, Hunt S, Deloukas P, Bentley DR, Donnelly P: The fine-scale structure of recombination rate variation in the human genome. Science 2004;304:581–584.
  43. Przeworski M: The signature of positive selection at randomly chosen loci. Genetics 2002;162:2053.
  44. Lonjou C, Zhang W, Collins A, Tapper WJ, Elahi E, Maniatis N, Morton NE: Linkage disequilibrium in human populations. Proc Natl Acad Sci USA 2003;100:6069–6074.
  45. Maniatis N, Collins A, Gibson J, Zhang W, Tapper W, Morton NE: Positional cloning by linkage disequilibrium. Am J Hum Genet 2004;74:846–855.

 goto top of outline Author Contacts

Andrew Collins
Human Genetics, School of Medicine
University of Southampton
Southampton SO16 6YD (UK)
Tel. +44 23 80 796939, Fax +44 23 80 794264, E-Mail arc@soton.ac.uk


 goto top of outline Article Information

Received: April 23, 2004
Accepted after revision: June 22, 2004
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 0, Number of References : 45


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 58, No. 1, Year 2004 (Cover Date: Released December 2004)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.ch/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

We examine the current effort to develop a haplotype map of the human genome and suggest an alternative approach which represents linkage disequilibrium patterns in the form of a metric LD map. LD maps have some of the useful properties of genetic linkage maps but have a much higher resolution which is optimal for SNP-based association mapping of common diseases. The studies that have been undertaken to date suggest that LD and recombination maps show some close similarities because of abundant, narrow, recombination hot spots. These hot spots are co-localised in all populations but, unlike linkage maps, LD maps differ in scale for different populations because of differences in population history. The prospects for developing optimized panels of SNPs and the use of linkage disequilibrium maps in disease gene localisation are assessed in the light of recent evidence.



 goto top of outline Author Contacts

Andrew Collins
Human Genetics, School of Medicine
University of Southampton
Southampton SO16 6YD (UK)
Tel. +44 23 80 796939, Fax +44 23 80 794264, E-Mail arc@soton.ac.uk


 goto top of outline Article Information

Received: April 23, 2004
Accepted after revision: June 22, 2004
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 0, Number of References : 45


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 58, No. 1, Year 2004 (Cover Date: Released December 2004)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.ch/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. Lonjou C, Collins A, Ajioka RS, Jorde LB, Kushner JP, Morton NE: Allelic association under map error and recombinational heterogeneity: A tale of two sites. Proc Natl Acad Sci USA 1998;95:11366–11370.
  2. Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 1996;273:1516–1517.
  3. Van Eerdewegh P, et al: Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002;418:426–439.
  4. Altshuler D, et al: The common PPAR gamma Pro12A1a polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000;26:76–80.
  5. Stefansson H, et al: Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002;71:877–892.
  6. Rioux JD, et al: Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001;29:223–228.
  7. Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG: Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 2001;357:1925–1928.
  8. Pritchard JK: Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001;69:124–137.
  9. Lander ES: The new genomics: global views of biology. Science 1996;274:536–539.
  10. Kruglyak L: Genetic isolates: Separate but equal? Proc Natl Acad Sci USA 1999;96:1170–1172.
  11. Kruglyak L: Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999;22:139–144.
  12. Lonjou C, Collins A, Morton NE: Allelic association between marker loci. Proc Natl Acad Sci USA 1999;96:1621–1626.
  13. Collins A, Lonjou C, Morton NE: Genetic epidemiology of single nucleotide polymorphisms. Proc Natl Acad Sci USA 1999;96:15173–15177.
  14. Service SK, Ophoff RA, Freimer NB: The genome-wide distribution of background linkage disequilibrium in a population isolate. Hum Mol Genet 2001;10:545–551
  15. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES: Linkage disequilibrium in the human genome. Nature 2001;411:199–204.
  16. De La Vega FM, Avi-Itzhak H, Halldorsson B, Scafe C, Istrail S, Gilbert DA, Spier EG: Distribution, sharing, and ancestry of common haplotypes in African-American, Caucasian and Asian populations. Am J Hum Genet 2003;73(5):267.
  17. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES: High-resolution haplotype structure in the human genome. Nat Genet 2001;29:229–232.
  18. The International HapMap Consortium: The International HapMap project. Nature 2003;426:789–796.
  19. Johnson GCL, et al: Haplotype tagging for the identification of common disease genes. Nature Genet 2001;29:233–237.
  20. Gabriel SB, et al: The structure of haplotype blocks in the human genome. Science 2002;296:2225–2229.
  21. Botstein D, Risch N: Discovering genotypes underlying human phenotypes: Past successes for mendelian disease, future approaches for complex disease. Nat Genet Suppl 2003;33:228–237.
  22. Patil N, et al: Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 2001;294:1719–1723.
  23. Zhang K, et al: A dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci USA 2002;99:7335–7339.
  24. Mannila H, Koivisto M, Perola M, Varilo T, Hennah W, Ekelund J, Lukk M, Peltonen L, Ukkonen E: Minimum description length block finder, a method to identify haplotype blocks and to compare the strength of block boundaries. Am J Hum Genet 2003;73:86–94.
  25. Phillips MS, Lawrence R, Sachidanandam R, Morris AP, Balding DJ, Donaldson MA, Studebaker JF, Ankener WM, Alfisi SV, Kuo FS, et al: Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots. Nat Genet 2003;33:382–387.
  26. Ke X, Hunt S, Tapper W, Lawrence R, Stavrides G, Ghori J, Whittaker P, Collins A, Morris AP, Bentley D, Cardon LR, Deloukas P: The impact of SNP density on fine-scale patterns of linkage disequilibrium. Hum Mol Genet 2004;13:577–588.
  27. Wang N, Akey JM, Zhang K, Chakraborty R, Jin L: Distribution of recombination crossovers and the origin of haplotype blocks: The interplay of population history, recombination and mutation. Am J Hum Genet 2002;71:1227–1234.
  28. Wall JD, Pritchard JK: Haplotype blocks and linkage disequiulibrium in the human genome. Nat Rev Genet 2003;4:587–597.
  29. Kauppi L, Sajantila A, Jeffreys AJ: Recombination hotspots rather than population history dominate linkage disequilibrium in the MHC class II region. Hum Mol Genet 2003;12:33–40.
  30. Oota H, Pakstis AJ, Bonne-Tamir B, Goldman D, Grigorenko E, Kajuna SL, Karoma NJ, Kungulilo S, Lu RB, Odunsi K, Okonofua F, Zhukova OV, Kidd JR, Kidd KK: The evolution and population genetics of the ALDH2 locus: random genetic drift, selection, and low levels of recombination. Ann Hum Genet 2004;68:93–109.
  31. Morton NE, Zhang W, Taillon-Miller P, Ennis S, Kwok P-Y, Collins A: The optimal measure of allelic association. Proc Natl Acad Sci USA 2001;98:5217–5222.
  32. Malecot G: The Mathematics of Heredity. San Francisco, Freeman, 1969.
  33. Collins A, Morton NE: Mapping a disease locus by allelic association. Proc Natl Acad Sci USA 1998;95:1741–1745.
  34. Shete S: A note on the optimal measure of allelic association. Ann Hum Genet 2003;67:189–191.
  35. Devlin B, Risch N: A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 1995;29:311–322.
  36. Jeffreys AJ, Kauppi L, Neumann R: Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex, Nat Genet 2001;29:217–222.
  37. Maniatis N, Collins A, Ku X-F, McCarthy LC, Hewett DR, Tapper W, Ennis S, Ke X, Morton NE: The first linkage disequilibrium (LD) maps: Delineation of hot and cold blocks by diplotype analysis. Proc Natl Acad Sci USA 2002;99:2228–2233.
  38. Tapper WJ, Morton NE, Dunham I, Ke X, Collins A: A sequence-based map of chromosome 22. Genome Res 2001;11:1290–1295.
  39. Dawson E, et al: A first-generation linkage disequilibrium map of human chromosome 22. Nature 2002;418:544–548.
  40. Kong, et al: A high-resolution recombination map of the human genome. Nature Genet 2002;31:241–247.
  41. Li N, Stephens M: Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 2003;165:2213–2233.
  42. McVean GAT, Myers SR, Hunt S, Deloukas P, Bentley DR, Donnelly P: The fine-scale structure of recombination rate variation in the human genome. Science 2004;304:581–584.
  43. Przeworski M: The signature of positive selection at randomly chosen loci. Genetics 2002;162:2053.
  44. Lonjou C, Zhang W, Collins A, Tapper WJ, Elahi E, Maniatis N, Morton NE: Linkage disequilibrium in human populations. Proc Natl Acad Sci USA 2003;100:6069–6074.
  45. Maniatis N, Collins A, Gibson J, Zhang W, Tapper W, Morton NE: Positional cloning by linkage disequilibrium. Am J Hum Genet 2004;74:846–855.