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The Rise and Fall and Rise of Linkage Analysis as a Technique for Finding and Characterizing Inherited Influences on Disease Expression

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Disease Gene Identification

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1706))

Abstract

For many years, family-based studies using linkage analysis represented the primary approach for identifying disease genes. This strategy is responsible for the identification of the greatest number of genes proven to cause human disease. However, technical advancements in next generation sequencing and high throughput genotyping, coupled with the apparent simplicity of association testing, led to the rejection of family-based studies and of linkage analysis. At present, genetic association methods, using case–control comparisons, have become the exclusive approach for detecting disease-related genes, particularly those underlying common, complex diseases. In this chapter, we present a historical overview of linkage analysis, including a description of how the approach works, as well as its strengths and weaknesses. We discuss how the transition from family-based studies to population comparison association studies led to a critical loss of information with respect to genetic etiology and inheritance, and we present historical and contemporary examples of linkage analysis “success stories” in identifying genes contributing to the development of human disease. Currently, linkage analysis is re-emerging as a useful approach for identifying disease genes, determining genetic parameters, and resolving genetic heterogeneity. We posit that the combination of linkage analysis, association testing, and high throughput sequencing provides a powerful approach for identifying disease-causing genes.

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References

  1. Greenberg DA (1993) Linkage analysis of “necessary” disease loci versus “susceptibility” loci. Am J Hum Genet 52:135–143

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Vieland VJ, Devoto M (2011) Next-generation linkage analysis. Hum Hered 72:227

    Article  PubMed  Google Scholar 

  3. Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247

    Article  CAS  PubMed  Google Scholar 

  4. Flannick J, Johansson S, Njolstad PR (2016) Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Nat Rev Endocrinol 12:394–406

    Article  CAS  PubMed  Google Scholar 

  5. Greenberg DA, Stewart WC (2012) How should we be searching for genes for common epilepsy? A critique and a prescription. Epilepsia 53(Suppl 4):72–80

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rodriguez-Murillo L, Greenberg DA (2008) Genetic association analysis: a primer on how it works, its strengths and its weaknesses. Int J Androl 31:546–556

    Article  PubMed  Google Scholar 

  7. Ott J (1999) Analysis of human genetic linkage, 3rd edn. Johns Hopkins University Press, Baltimore, MD

    Google Scholar 

  8. Mielcarek M (2015) Huntington’s disease is a multi-system disorder. Rare Dis 3:e1058464

    Article  PubMed  PubMed Central  Google Scholar 

  9. Corso B, Greenberg DA (2014) Using linkage analysis to detect gene-gene interaction by stratifying family data on known disease, or disease-associated, alleles. PLoS One 9:e93398

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hodge SE, Hager VR, Greenberg DA (2016) Using Linkage Analysis to Detect Gene-Gene Interactions. 2. Improved Reliability and Extension to More-Complex Models. PLoS One 11:e0146240

    Article  PubMed  PubMed Central  Google Scholar 

  11. Greenberg DA (1989) Inferring mode of inheritance by comparison of lod scores. Am J Med Genet 34:480–486

    Article  CAS  PubMed  Google Scholar 

  12. Greenberg DA (1990) Linkage analysis assuming a single-locus mode of inheritance for traits determined by two loci: inferring mode of inheritance and estimating penetrance. Genet Epidemiol 7:467–479

    Article  CAS  PubMed  Google Scholar 

  13. Greenberg DA, Abreu PC (2001) Determining trait locus position from multipoint analysis: accuracy and power of three different statistics. Genet Epidemiol 21:299–314

    Article  CAS  PubMed  Google Scholar 

  14. Whittemore AS (1996) Genome scanning for linkage: an overview. Am J Hum Genet 59:704–716

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Greenberg DA, Abreu P, Hodge SE (1998) The power to detect linkage in complex disease by means of simple LOD-score analyses. Am J Hum Genet 63:870–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hodge SE, Greenberg DA (1992) Sensitivity of lod scores to changes in diagnostic status. Am J Hum Genet 50:1053–1066

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Cordell HJ (2009) Detecting gene-gene interactions that underlie human diseases. Nat Rev Genet 10:392–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kooperberg C, Leblanc M, Dai JY, Rajapakse I (2009) Structures and assumptions: strategies to harness gene x gene and gene x environment interactions in GWAS. Stat Sci 24:472–488

    Article  PubMed  PubMed Central  Google Scholar 

  19. Musani SK, Shriner D, Liu N, Feng R, Coffey CS, Yi N, Tiwari HK, Allison DB (2007) Detection of gene x gene interactions in genome-wide association studies of human population data. Hum Hered 63:67–84

    Article  CAS  PubMed  Google Scholar 

  20. Rodriguez-Murillo L, Subaran R, Stewart WC, Pramanik S, Marathe S, Barst RJ, Chung WK, Greenberg DA (2010) Novel loci interacting epistatically with bone morphogenetic protein receptor 2 cause familial pulmonary arterial hypertension. J Heart Lung Transplant 29:174–180

    Article  PubMed  Google Scholar 

  21. Balding DJ (2006) A tutorial on statistical methods for population association studies. Nat Rev Genet 7:781–791

    Article  CAS  PubMed  Google Scholar 

  22. Slatkin M (2008) Linkage disequilibrium--understanding the evolutionary past and mapping the medical future. Nat Rev Genet 9:477–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lewontin RC (1995) The detection of linkage disequilibrium in molecular sequence data. Genetics 140:377–388

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Jorde LB (2000) Linkage disequilibrium and the search for complex disease genes. Genome Res 10:1435–1444

    Article  CAS  PubMed  Google Scholar 

  25. Marchini J, Cardon LR, Phillips MS, Donnelly P (2004) The effects of human population structure on large genetic association studies. Nat Genet 36:512–517

    Article  CAS  PubMed  Google Scholar 

  26. Sasieni PD (1997) From genotypes to genes: doubling the sample size. Biometrics 53:1253–1261

    Article  CAS  PubMed  Google Scholar 

  27. Weiss KM, Clark AG (2002) Linkage disequilibrium and the mapping of complex human traits. Trends Genet 18:19–24

    Article  CAS  PubMed  Google Scholar 

  28. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B (1988) Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 29:990–996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Thompson NP, Driscoll R, Pounder RE, Wakefield AJ (1996) Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 312:95–96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Orholm M, Binder V, Sorensen TI, Rasmussen LP, Kyvik KO (2000) Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 35:1075–1081

    Article  CAS  PubMed  Google Scholar 

  31. Spehlmann ME, Begun AZ, Burghardt J, Lepage P, Raedler A, Schreiber S (2008) Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study. Inflamm Bowel Dis 14:968–976

    Article  PubMed  Google Scholar 

  32. Pokorny RM, Hofmeister A, Galandiuk S, Dietz AB, Cohen ND, Neibergs HL (1997) Crohn’s disease and ulcerative colitis are associated with the DNA repair gene MLH1. Ann Surg 225:718–723. discussion 723–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Franchimont D, Belaiche J, Louis E, Simon S, GrandBastien B, Gower-Rousseau C, Fontaine F, Delforge M (1997) Familial Crohn’s disease: a study of 18 families. Acta Gastroenterol Belg 60:134–137

    CAS  PubMed  Google Scholar 

  34. Polito JM II, Rees RC, Childs B, Mendeloff AI, Harris ML, Bayless TM (1996) Preliminary evidence for genetic anticipation in Crohn’s disease. Lancet 347:798–800

    Article  PubMed  Google Scholar 

  35. Polito JM II, Childs B, Mellits ED, Tokayer AZ, Harris ML, Bayless TM (1996) Crohn’s disease: influence of age at diagnosis on site and clinical type of disease. Gastroenterology 111:580–586

    Article  PubMed  Google Scholar 

  36. Hugot JP, Laurent-Puig P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, Naom I, Dupas JL, Van Gossum A, Orholm M, Bonaiti-Pellie C, Weissenbach J, Mathew CG, Lennard-Jones JE, Cortot A, Colombel JF, Thomas G (1996) Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 379:821–823

    Article  CAS  PubMed  Google Scholar 

  37. Ohmen JD, Yang HY, Yamamoto KK, Zhao HY, Ma Y, Bentley LG, Huang Z, Gerwehr S, Pressman S, McElree C, Targan S, Rotter JI, Fischel-Ghodsian N (1996) Susceptibility locus for inflammatory bowel disease on chromosome 16 has a role in Crohn’s disease, but not in ulcerative colitis. Hum Mol Genet 5:1679–1683

    Article  CAS  PubMed  Google Scholar 

  38. Parkes M, Satsangi J, Lathrop GM, Bell JI, Jewell DP (1996) Susceptibility loci in inflammatory bowel disease. Lancet 348:1588

    Article  CAS  PubMed  Google Scholar 

  39. Mirza MM, Lee J, Teare D, Hugot JP, Laurent-Puig P, Colombel JF, Hodgson SV, Thomas G, Easton DF, Lennard-Jones JE, Mathew CG (1998) Evidence of linkage of the inflammatory bowel disease susceptibility locus on chromosome 16 (IBD1) to ulcerative colitis. J Med Genet 35:218–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brant SR, Fu Y, Fields CT, Baltazar R, Ravenhill G, Pickles MR, Rohal PM, Mann J, Kirschner BS, Jabs EW, Bayless TM, Hanauer SB, Cho JH (1998) American families with Crohn’s disease have strong evidence for linkage to chromosome 16 but not chromosome 12. Gastroenterology 115:1056–1061

    Article  CAS  PubMed  Google Scholar 

  41. Curran ME, Lau KF, Hampe J, Schreiber S, Bridger S, Macpherson AJ, Cardon LR, Sakul H, Harris TJ, Stokkers P, Van Deventer SJ, Mirza M, Raedler A, Kruis W, Meckler U, Theuer D, Herrmann T, Gionchetti P, Lee J, Mathew C, Lennard-Jones J (1998) Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16. Gastroenterology 115:1066–1071

    Article  CAS  PubMed  Google Scholar 

  42. Annese V, Latiano A, Bovio P, Forabosco P, Piepoli A, Lombardi G, Andreoli A, Astegiano M, Gionchetti P, Riegler G, Sturniolo GC, Clementi M, Rappaport E, Fortina P, Devoto M, Gasparini P, Andriulli A (1999) Genetic analysis in Italian families with inflammatory bowel disease supports linkage to the IBD1 locus--a GISC study. Eur J Hum Genet 7:567–573

    Article  CAS  PubMed  Google Scholar 

  43. Cavanaugh J, Consortium IBDIG (2001) International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Genet 68:1165–1171

    Article  CAS  PubMed  Google Scholar 

  44. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–1689

    Article  CAS  PubMed  Google Scholar 

  45. Narod SA, Amos C (1990) Estimating the power of linkage analysis in hereditary breast cancer. Am J Hum Genet 46:266–272

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Easton DF, Bishop DT, Ford D, Crockford GP (1993) Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52:678–701

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Brown MA, Solomon E (1994) Towards cloning the familial breast-ovarian cancer gene on chromosome 17. Curr Opin Genet Dev 4:439–445

    Article  CAS  PubMed  Google Scholar 

  48. Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517

    Article  CAS  PubMed  Google Scholar 

  49. Cuyvers E, Sleegers K (2016) Genetic variations underlying Alzheimer’s disease: evidence from genome-wide association studies and beyond. Lancet Neurol 15:857–868

    Article  CAS  PubMed  Google Scholar 

  50. Karaderi T, Drong AW, Lindgren CM (2015) Insights into the genetic susceptibility to type 2 diabetes from genome-wide association studies of obesity-related traits. Curr Diab Rep 15:83

    Article  PubMed  PubMed Central  Google Scholar 

  51. Astradsson A, Olafsson E, Ludvigsson P, Bjorgvinsson H, Hauser WA (1998) Rolandic epilepsy: an incidence study in Iceland. Epilepsia 39:884–886

    Article  CAS  PubMed  Google Scholar 

  52. Sidenvall R, Forsgren L, Heijbel J (1996) Prevalence and characteristics of epilepsy in children in northern Sweden. Seizure 5:139–146

    Article  CAS  PubMed  Google Scholar 

  53. Heijbel J, Blom S, Rasmuson M (1975) Benign epilepsy of childhood with centrotemporal EEG foci: a genetic study. Epilepsia 16:285–293

    Article  CAS  PubMed  Google Scholar 

  54. Bali B, Kull LL, Strug LJ, Clarke T, Murphy PL, Akman CI, Greenberg DA, Pal DK (2007) Autosomal dominant inheritance of centrotemporal sharp waves in rolandic epilepsy families. Epilepsia 48:2266–2272

    PubMed  PubMed Central  Google Scholar 

  55. Echenne B, Cheminal R, Rivier F, Negre C, Touchon J, Billiard M (1992) Epileptic electroencephalographic abnormalities and developmental dysphasias: a study of 32 patients. Brain Dev 14:216–225

    Article  CAS  PubMed  Google Scholar 

  56. Holtmann M, Becker K, Kentner-Figura B, Schmidt MH (2003) Increased frequency of rolandic spikes in ADHD children. Epilepsia 44:1241–1244

    Article  PubMed  Google Scholar 

  57. Scabar A, Devescovi R, Blason L, Bravar L, Carrozzi M (2006) Comorbidity of DCD and SLI: significance of epileptiform activity during sleep. Child Care Health Dev 32:733–739

    Article  CAS  PubMed  Google Scholar 

  58. Strug LJ, Clarke T, Chiang T, Chien M, Baskurt Z, Li W, Dorfman R, Bali B, Wirrell E, Kugler SL, Mandelbaum DE, Wolf SM, McGoldrick P, Hardison H, Novotny EJ, Ju J, Greenberg DA, Russo JJ, Pal DK (2009) Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4). Eur J Hum Genet 17:1171–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Panjwani N, Wilson MD, Addis L, Crosbie J, Wirrell E, Auvin S, Caraballo RH, Kinali M, McCormick D, Oren C, Taylor J, Trounce J, Clarke T, Akman CI, Kugler SL, Mandelbaum DE, McGoldrick P, Wolf SM, Arnold P, Schachar R, Pal DK, Strug LJ (2016) A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy. Ann Clin Transl Neurol 3:512–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pal DK, Li W, Clarke T, Lieberman P, Strug LJ (2010) Pleiotropic effects of the 11p13 locus on developmental verbal dyspraxia and EEG centrotemporal sharp waves. Genes Brain Behav 9:1004–1012

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Center for Genes, Environment, and Health, National Jewish Health, 1400 Jackson Street, Denver, CO, 80602, USA

    Ettie M. Lipner

  2. Department of Pharmacology, University of Colorado Denver, School of Medicine, Aurora, CO, USA

    Ettie M. Lipner

  3. Battelle Center for Mathematical Medicine, Nationwide Children’s Hospital, Columbus, OH, USA

    David A. Greenberg

  4. Department of Pediatrics, Wexner Medical Center, Ohio State University, Columbus, OH, USA

    David A. Greenberg

Authors
  1. Ettie M. Lipner
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  2. David A. Greenberg
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Correspondence to Ettie M. Lipner .

Editor information

Editors and Affiliations

  1. Translational Genomics Research Institute, Phoenix, Arizona, USA

    Johanna K. DiStefano

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Lipner, E.M., Greenberg, D.A. (2018). The Rise and Fall and Rise of Linkage Analysis as a Technique for Finding and Characterizing Inherited Influences on Disease Expression. In: DiStefano, J. (eds) Disease Gene Identification. Methods in Molecular Biology, vol 1706. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7471-9_21

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  • DOI: https://doi.org/10.1007/978-1-4939-7471-9_21

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7470-2

  • Online ISBN: 978-1-4939-7471-9

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