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.

  • Original Article
  • Published:

Follow-up investigation of 12 proposed linkage regions in multiple sclerosis

Genes & Immunity volume 7, pages 366–371 (2006)Cite this article

Abstract

Multiple sclerosis (MS) is an autoimmune disease with overwhelming evidence for genetic determination, and for which a maternal parent-of-origin effect has been reported. As with many complex diseases, multiple suggestive linkage signals have been observed. However, the only unambiguous association and linkage identified to date is with alleles of the human lymphocyte antigen (HLA) class II region. We have now carried out high-density microsatellite genotyping for 12 of the most promising regions (1p, 1q, 2q, 4q, 5p, 9q, 10p, 11p, 12q, 17q, 18p, 19p) from a whole-genome scan in 552 affected sibling pairs. This has been carried out in 194 families containing avuncular pairs. These permit examination of parent-of-origin effects in non-colineal pairs when divided into likely maternal and paternal trait transmission. The results do not confirm any non-major histocompatibility complex linkage in the overall subset nor in the maternal, paternal or HLA-DRB1*1501 subsets. We were able to establish exclusion for a locus with λAV⩾1.3 for all the previously suggested regions. These results again raise the possibility that the paradigm of multiple genes of small individual effect used to justify genome searches in MS is incorrect.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Sadovnick AD, Yee IM, Ebers GC . Multiple sclerosis and birth order: a longitudinal cohort study. Lancet Neurol 2005; 4: 611–617.

    Article  PubMed  Google Scholar 

  2. Ebers GC, Yee IM, Sadovnick AD, Duquette P . Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group. Ann Neurol 2000; 48: 927–931.

    Article  CAS  PubMed  Google Scholar 

  3. Ebers GC, Sadovnick AD, Dyment DA, Yee IM, Willer CJ, Risch N . Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 2004; 363: 1773–1774.

    Article  CAS  PubMed  Google Scholar 

  4. Nielsen NM, Westergaard T, Rostgaard K, Frisch M, Hjalgrim H, Wohlfahrt J et al. Familial risk of multiple sclerosis: a nationwide cohort study. Am J Epidemiol 2005; 162: 774–778.

    Article  PubMed  Google Scholar 

  5. Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC . Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci USA 2003; 100: 12877–12882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dyment DA, Herrera BM, Cader MZ, Willer CJ, Lincoln MR, Sadovnick AD et al. Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. Hum Mol Genet 2005; 14: 2019–2026.

    Article  CAS  PubMed  Google Scholar 

  7. Colhoun HM, McKeigue PM, Davey Smith G . Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361: 865–872.

    Article  PubMed  Google Scholar 

  8. Ligers A, Dyment DA, Willer CJ, Sadovnick AD, Ebers G, Risch N et al. Evidence of linkage with HLA-DR in DRB1*1501-negative families with multiple sclerosis. Am J Hum Genet 2001; 69: 900–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dyment DA, Sadovnick AD, Willer CJ, Armstrong H, Cader ZM, Wiltshire S et al. An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group. Hum Mol Genet 2004; 13: 1005–1015.

    Article  CAS  PubMed  Google Scholar 

  10. Sadovnick AD, Yee IM, Ebers GC, Risch NJ . Effect of age at onset and parental disease status on sibling risks for MS. Neurology 1998; 50: 719–723.

    Article  CAS  PubMed  Google Scholar 

  11. Kantarci O, Barcellos LF, Oksenberg JR, Atkinson EJ, Lincoln RR, deAndrade M et al. Affected males transmit multiple sclerosis more often to children than affected females: the Carter effect. Mult Scler 2004; 10 (Suppl 2): S97–S283.

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Ebers GC, Bulman DE, Sadovnick AD, Paty DW, Warren S, Hader W et al. A population-based study of multiple sclerosis in twins. N Engl J Med 1986; 315: 1638–1642.

    Article  CAS  PubMed  Google Scholar 

  14. Ebers GC, Koopman WJ, Hader W, Sadovnick AD, Kremenchutzky M, Mandalfino P et al. The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis. Brain 2000; 123 (Part 3): 641–649.

    Article  PubMed  Google Scholar 

  15. Haines JL, Bradford Y, Garcia ME, Reed AD, Neumeister E, Pericak-Vance MA et al. Multiple susceptibility loci for multiple sclerosis. Hum Mol Genet 2002; 11: 2251–2256.

    Article  CAS  PubMed  Google Scholar 

  16. Kenealy SJ, Herrel LA, Bradford Y, Schnetz-Boutaud N, Oksenberg JR, Hauser SL et al. Examination of seven candidate regions for multiple sclerosis: strong evidence of linkage to chromosome 1q44. Genes Immun 2006: 73–76.

    Article  Google Scholar 

  17. Sawcer S, Ban M, Maranian M, Yeo TW, Compston A, Kirby A et al. A high-density screen for linkage in multiple sclerosis. Am J Hum Genet 2005; 77: 454–467.

    Article  PubMed  Google Scholar 

  18. Sadovnick AD, Risch NJ, Ebers GC . Canadian Collaborative Project on genetic susceptibility to MS, phase 2: rationale and method. Canadian Collaborative Study Group. Can J Neurol Sci 1998; 25: 216–221.

    Article  CAS  PubMed  Google Scholar 

  19. O'Connell Jr WD . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . MERLIN – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

    Article  CAS  PubMed  Google Scholar 

  21. Mukhopadhyay N, Almasy L, Schroeder M, Mulvihill WP, Weeks DE . Mega2: data-handling for facilitating genetic linkage and association analyses. Bioinformatics 2005; 21: 2556–2557.

    Article  CAS  PubMed  Google Scholar 

  22. Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997; 61: 1179–1188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hinds DA, Risch N . The ASPEX package: affected sib-pair exclusion mapping. http://aspex.sourceforge.net/. 1996.

  24. Chataway J, Feakes R, Coraddu F, Gray J, Deans J, Fraser M et al. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen. Brain 1998; 121 (Part 10): 1869–1887.

    Article  PubMed  Google Scholar 

  25. Hensiek AE, Roxburgh R, Smilie B, Coraddu F, Akesson E, Holmans P et al. Updated results of the United Kingdom linkage-based genome screen in multiple sclerosis. J Neuroimmunol 2003; 143: 25–30.

    Article  CAS  PubMed  Google Scholar 

  26. Kenealy SJ, Babron MC, Bradford Y, Schnetz-Boutaud N, Haines JL, Rimmler JB et al. A second-generation genomic screen for multiple sclerosis. Am J Hum Genet 2004; 75: 1070–1078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pericak-Vance MA, Rimmler JB, Haines JL, Garcia ME, Oksenberg JR, Barcellos LF et al. Investigation of seven proposed regions of linkage in multiple sclerosis: an American and French collaborative study. Neurogenetics 2004; 5: 45–48.

    Article  PubMed  Google Scholar 

  28. Dyment DA, Willer CJ, Scott B, Armstrong H, Ligers A, Hillert J et al. Genetic susceptibility to MS: a second stage analysis in Canadian MS families. Neurogenetics 2001; 3: 145–151.

    Article  CAS  PubMed  Google Scholar 

  29. Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet 1996; 13: 464–468.

    Article  CAS  PubMed  Google Scholar 

  30. Akesson E, Oturai A, Berg J, Fredrikson S, Andersen O, Harbo HF et al. A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis. Genes Immun 2002; 3: 279–285.

    Article  CAS  PubMed  Google Scholar 

  31. Coraddu F, Sawcer S, D'Alfonso S, Lai M, Hensiek A, Solla E et al. A genome screen for multiple sclerosis in Sardinian multiplex families. Eur J Hum Genet 2001; 9: 621–626.

    Article  CAS  PubMed  Google Scholar 

  32. Broadley S, Sawcer S, D'Alfonso S, Hensiek A, Coraddu F, Gray J et al. A genome screen for multiple sclerosis in Italian families. Genes Immun 2001; 2: 205–210.

    Article  CAS  PubMed  Google Scholar 

  33. Ban M, Stewart GJ, Bennetts BH, Heard R, Simmons R, Maranian M et al. A genome screen for linkage in Australian sibling-pairs with multiple sclerosis. Genes Immun 2002; 3: 464–469.

    Article  CAS  PubMed  Google Scholar 

  34. Haines JL, Ter-Minassian M, Bazyk A, Gusella JF, Kim DJ, Terwedow H et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group. Nat Genet 1996; 13: 469–471.

    Article  CAS  PubMed  Google Scholar 

  35. Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C et al. A full genome search in multiple sclerosis. Nat Genet 1996; 13: 472–476.

    Article  CAS  PubMed  Google Scholar 

  36. D'Alfonso S, Nistico L, Zavattari P, Marrosu MG, Murru R, Lai M et al. Linkage analysis of multiple sclerosis with candidate region markers in Sardinian and Continental Italian families. Eur J Hum Genet 1999; 7: 377–385.

    Article  CAS  PubMed  Google Scholar 

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

  38. Kuokkanen S, Gschwend M, Rioux JD, Daly MJ, Terwilliger JD, Tienari PJ et al. Genomewide scan of multiple sclerosis in Finnish multiplex families. Am J Hum Genet 1997; 61: 1379–1387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Oturai A, Larsen F, Ryder LP, Madsen HO, Hillert J, Fredrikson S et al. Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis. Ann Neurol 1999; 46: 612–616.

    Article  CAS  PubMed  Google Scholar 

  40. Xu C, Dai Y, Fredrikson S, Hillert J . Association and linkage analysis of candidate chromosomal regions in multiple sclerosis: indication of disease genes in 12q23 and 7ptr-15. Eur J Hum Genet 1999; 7: 110–116.

    Article  CAS  PubMed  Google Scholar 

  41. Xu C, Dai Y, Lorentzen JC, Dahlman I, Olsson T, Hillert J . Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci. Eur J Hum Genet 2001; 9: 458–463.

    Article  CAS  PubMed  Google Scholar 

  42. Modin H, Masterman T, Thorlacius T, Stefansson M, Jonasdottir A, Stefansson K et al. Genome-wide linkage screen of a consanguineous multiple sclerosis kinship. Mult Scler 2003; 9: 128–134.

    Article  CAS  PubMed  Google Scholar 

  43. Akesson E, Coraddu F, Marrosu MG, Massacesi L, Hensiek A, Harbo HF et al. Refining the linkage analysis on chromosome 10 in 449 sib-pairs with multiple sclerosis. J Neuroimmunol 2003; 143: 31–38.

    Article  CAS  PubMed  Google Scholar 

  44. Vitale E, Cook S, Sun R, Specchia C, Subramanian K, Rocchi M et al. Linkage analysis conditional on HLA status in a large North American pedigree supports the presence of a multiple sclerosis susceptibility locus on chromosome 12p12. Hum Mol Genet 2002; 11: 295–300.

    Article  CAS  PubMed  Google Scholar 

  45. GAMES, Cooperative at TMSG. A meta-analysis of whole genome linkage screens in multiple sclerosis. J Neuroimmunol 2003; 143: 39–46.

  46. Saarela J, Schoenberg Fejzo M, Chen D, Finnila S, Parkkonen M, Kuokkanen S et al. Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22–q24. Hum Mol Genet 2002; 11: 2257–2267.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The CCPGSMS is funded by the Multiple Sclerosis Society of Canada. BMH is funded by the UK MS society.

Author information

Authors and Affiliations

  1. The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    B M Herrera, M Z Cader, D A Dyment, J T Bell, S V Ramagopalan, M R Lincoln, S Orton, M J Chao & G C Ebers

  2. Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK

    B M Herrera, M Z Cader, D A Dyment, S V Ramagopalan, M R Lincoln, S Orton, M J Chao & G C Ebers

  3. Department of Medical Genetics and Faculty of Medicine Division of Neurology, University of British Columbia, UBC Hospital, Vancouver, British Columbia, Canada

    A D Sadovnick

Authors
  1. B M Herrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Z Cader
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D A Dyment
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J T Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S V Ramagopalan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M R Lincoln
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Orton
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M J Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A D Sadovnick
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G C Ebers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G C Ebers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herrera, B., Cader, M., Dyment, D. et al. Follow-up investigation of 12 proposed linkage regions in multiple sclerosis. Genes Immun 7, 366–371 (2006). https://doi.org/10.1038/sj.gene.6364308

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364308

Keywords

This article is cited by

Search

Advanced search

Quick links