Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

A genome screen for linkage in Australian sibling-pairs with multiple sclerosis

Abstract

The role of genetic factors in determining susceptibility to multiple sclerosis is well established but, despite the global distribution of the disease, systematic efforts to locate susceptibility genes have concentrated exclusively on populations from the Northern Hemisphere. We performed a genome wide screen of linkage in the Australian population using a panel of 397 microsatellite markers in 54 affected sibling-pairs. Multipoint linkage analysis revealed four regions of suggestive linkage (on chromosomes 2p13, 4q26-28, 6q26 and Xp11) and 18 additional regions of potential linkage (at 1q43-44, 3q13-24, 4q24, 4q31-34, 5q11-13, 6q27, 7q33-35, 8p23-21, 9q21, 13q31-32, 16p13, 16p11, 16q23-24, 17p13, 18p11, 20p12-11, Xp21-11 and Xq23-28). Our results contribute to the available data adding new provisional regions of linkage as well as increasing support for areas previously implicated in genetic susceptibility to multiple sclerosis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Hogancamp WE, Rodriguez M, Weinshenker BG . The epidemiology of multiple sclerosis Mayo Clin Proc 1997 72: 871–878

    Article  CAS  Google Scholar 

  2. Sadovnick AD, Armstrong H, Rice GPA et al. A population based study of multiple sclerosis in twins: updated Ann Neurol 1993 33: 281–285

    Article  CAS  Google Scholar 

  3. Mumford CJ, Wood NW, Kellar-Wood HF et al. The British Isles survey of multiple sclerosis in twins Neurology 1994 44: 11–15

    Article  CAS  Google Scholar 

  4. Sadovnick AD, Ebers GC, Dyment DA, Risch NJ . the Canadian Collaborative Study Group. Evidence for genetic basis of multiple sclerosis Lancet 1996 347: 1728–1731

    Article  CAS  Google Scholar 

  5. Ebers GC, Sadovnick AD, Risch NJ . The Canadian Collaborative Study Group. A genetic basis for familial aggregation in multiple sclerosis Nature 1995 377: 150–151

    Article  CAS  Google Scholar 

  6. Dean G, McLoughlin H, Brady R, Adelstein A, Tallett-Williams J . Multiple sclerosis among immigrants in Greater London BMJ 1976 1: 861–864

    Article  CAS  Google Scholar 

  7. Hammond SR, de, Wytt C, Maxwell IC et al. The epidemiology of multiple sclerosis in Queensland, Australia J Neurol Sci 1987 80: 185–204

    Article  CAS  Google Scholar 

  8. Hammond SR, McLeod JG, Millingen KS et al. The epidemiology of multiple sclerosis in three Australian cities: Perth, Newcastle and Hobart Brain 1988 111: 1–25

    Article  Google Scholar 

  9. Sawcer SJ, Jones HB, Feakes R et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosomes 6p21 and 17q22 Nat Genet 1996 13: 464–468

    Article  CAS  Google Scholar 

  10. Haines JL, Ter-Minassian M, Bazyk A et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex Nat Genet 1996 13: 469–471

    Article  CAS  Google Scholar 

  11. Ebers GC, Kukay K, Bulman DE et al. A full genome search in multiple sclerosis Nat Genet 1996 13: 472–476

    Article  CAS  Google Scholar 

  12. Kuokkanen S, Gschwend M, Rioux JD et al. Genomewide scan of multiple sclerosis in Finnish multiplex families Am J Hum Genet 1997 61: 1379–1387

    Article  CAS  Google Scholar 

  13. Åkesson E, Oturai A, Berg J et al. A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis 2002 3: 279–285

  14. Broadley S, Sawcer S, D'Alfonso S et al. A genome screen for multiple sclerosis in Italian families Genes Immun 2001 2: 205–210

    Article  CAS  Google Scholar 

  15. Coraddu F, Sawcer S, D'Alfonso S et al. A genome screen for multiple sclerosis in Sardinian multiplex families Eur J Hum Genet 2001 9: 621–662

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Sawcer SJ, Jones HB, Judge D et al. Empirical genomewide significance levels established by whole genome simulations Genet Epidemiol 1997 14: 223–229

    Article  CAS  Google Scholar 

  18. The Transatlantic Multiple Sclerosis Genetics Cooperative. A meta-analysis of genome screens in multiple sclerosis Mult Scler 2001 7: 3–11

  19. Kellar-Wood H, Wood NW, Holmans P et al. Multiple sclerosis and the HLA-D region: linkage and association studies J Neuroimmunol 1995 58: 183–190

    Article  CAS  Google Scholar 

  20. Stewart GJ, Teutsch SM, Castle M, Heard RN, Bennetts BH . HLA-DR, -DQA1 and -DQB1 associations in Australian multiple sclerosis patients Eur J Immunogenet 1997 24: 81–92

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Feakes R, Sawcer S, Smillie B et al. No evidence for the involvement of Interleukin 2 or the immunoglobulin heavy chain cluster in determining susceptibility to multiple sclerosis J Neurol Neurosurg Psychiat 2000 68: 679

    Article  CAS  Google Scholar 

  23. Broadley SA, Deans J, Sawcer SJ, Clayton D, Compston DA . Autoimmune disease in first-degree relatives of patients with multiple sclerosis. A UK survey Brain 2000 123: 1102–1111

    Article  Google Scholar 

  24. Becker K, Simon R, Bailey-Wilson J et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases Proc Natl Acad Sci USA 1998 95: 9979–9984

    Article  CAS  Google Scholar 

  25. Jawaheer D, Seldin MF, Amos CI et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases Am J Hum Genet 2001 68: 927–936

    Article  CAS  Google Scholar 

  26. Tsao BP, Cantor RM, Kalunian KC et al. Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus J Clin Invest 1997 99: 725–731

    Article  CAS  Google Scholar 

  27. Gaffney P, Kearns G, Shark K et al. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families Proc Natl Acad Sci USA 1998 95: 14 875–14 879

    Article  Google Scholar 

  28. Moser K, Neas B, Salmon J et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees Proc Natl Acad Sci USA 1998 95: 14 869–14 874

    Article  Google Scholar 

  29. Cho JH, Nicolae DL, Gold LH et al. Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1 Proc Natl Acad Sci USA 1998 95: 7502–7507

    Article  CAS  Google Scholar 

  30. Cornelis F, Faure S, Martinez M et al. New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study Proc Natl Acad Sci USA 1998 95: 10 746–10 750

    Article  Google Scholar 

  31. Davies JL, Kawaguchi Y, Bennett ST et al. A genome-wide search for human type 1 diabetes susceptibility genes Nature 1994 371: 130–136

    Article  CAS  Google Scholar 

  32. Cucca F, Goy JV, Kawaguchi Y et al. A male–female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients Nat Genet 1998 19: 301–302

    Article  CAS  Google Scholar 

  33. Encinas JA, Lees MB, Sobel RA et al. Genetic analysis of susceptibility to experimental autoimmune encephalomyelitis in a cross between SJL/J and B10.S mice J Immunol 1996 157: 2186–2192

    CAS  PubMed  Google Scholar 

  34. Encinas JA, Wicker LS, Peterson LB et al. QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing IL2 Nat Genet 1999 21: 158–160

    Article  CAS  Google Scholar 

  35. Poser CM, Paty DW, Scheinberg L et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols Ann Neurol 1983 13: 227–231

    Article  CAS  Google Scholar 

  36. Holmans P, Clayton D . Efficiency of typing unaffected relatives in an affected sib-pair linkage study Am J Hum Genet 1995 57: 1221–1232

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lahiri DK, Nurnberger Jr JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies Nucl Acids Res 1991 19: 5444

    Article  CAS  Google Scholar 

  38. Kruglyak L, Lander ES . Complete multipoint sib-pair analysis of qualitative and quantitative traits Am J Hum Genet 1995 57: 439–454

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ehm M, Wagner M . A test statistic to detect errors in sib-pair relationships Am J Hum Genet 1998 62: 181–188

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S Adams, V Perich, N Hartley, M Bugeja, S Surkus and S Teutsch for the collection and preparation of the DNA samples, J Gray for valuable technical support and the Neurologists of Australia for verifying the diagnosis of the patients. This work was supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland (Grant No 659/01), the Wellcome Trust (Grant No 057097/Z/99Z), and the National Health and Medical Research Council of Australia (Grant No 981580 and 153990).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G J Stewart.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ban, M., Stewart, G., Bennetts, B. et al. A genome screen for linkage in Australian sibling-pairs with multiple sclerosis. Genes Immun 3, 464–469 (2002). https://doi.org/10.1038/sj.gene.6363910

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6363910

Keywords

This article is cited by

Search

Quick links