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Philos Trans R Soc Lond B Biol Sci. Oct 29, 1999; 354(1390): 1623–1634.
PMCID: PMC1692683

The genetic epidemiology of multiple sclerosis.

Abstract

Epidemiological studies have implicated an interplay between genetic and environmental factors in the aetiology of multiple sclerosis (MS). There is a familial recurrence rate of approximately 15%. Meta-analysis of the recurrence risk shows that the rate is highest overall for siblings, then parents and children, with lower rates in second- and third-degree relatives. Recurrence is highest for monozygotic twins. Conversely, the frequency in adoptees is similar to the population lifetime risk. The age-adjusted risk for half siblings is also less than for full siblings. Recurrence is higher in the children of conjugal pairs with MS than the offspring of single affected. These classical genetic observations suggest that MS is a complex trait in which susceptibility is determined by several genes acting independently or epistatically. Comparisons between co-affected sibling pairs provide no evidence for correlation with age or year at onset and mode of presentation or disability. Thus far, the identification of susceptibility genes has proved elusive but genetic strategies are now in place which should illuminate the problem. The main dividend will be an improved understanding of the pathogenesis. To date, population studies have demonstrated an association between the class II major histocompatibility complex (MHC) alleles DR15 and DQ6 and their corresponding genotypes. An association with DR4, with or without the primary DR15 link, is seen in some Mediterranean populations. Candidate gene approaches have otherwise proved unrewarding. Four groups of investigators have undertaken a systematic search of the genome. In common with most other complex traits, no major susceptibility gene has been identified but regions of interest have been provisionally identified. These genetic analyses are predicated on the assumption that MS is one disease. Genotypic and phenotypic analyses are beginning to question this assumption. A major part of future studies in the genetics of MS will be to resolve the question of disease heterogeneity.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Andersen O, Lygner PE, Bergström T, Andersson M, Vahlne A. Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study. J Neurol. 1993 Jul;240(7):417–422. [PubMed]
  • Barcellos LF, Thomson G, Carrington M, Schafer J, Begovich AB, Lin P, Xu XH, Min BQ, Marti D, Klitz W. Chromosome 19 single-locus and multilocus haplotype associations with multiple sclerosis. Evidence of a new susceptibility locus in Caucasian and Chinese patients. JAMA. 1997 Oct 15;278(15):1256–1261. [PubMed]
  • Becker KG, Simon RM, Bailey-Wilson JE, Freidlin B, Biddison WE, McFarland HF, Trent JM. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9979–9984. [PMC free article] [PubMed]
  • Benedikz J, Magnússon H, Guthmundsson G. Multiple sclerosis in Iceland, with observations on the alleged epidemic in the Faroe Islands. Ann Neurol. 1994 Dec;36 (Suppl 2):S175–S179. [PubMed]
  • Bennetts BH, Teutsch SM, Buhler MM, Heard RN, Stewart GJ. The CCR5 deletion mutation fails to protect against multiple sclerosis. Hum Immunol. 1997 Nov;58(1):52–59. [PubMed]
  • Bulman DE, Sadovnick AD, Ebers GC. Age of onset in siblings concordant for multiple sclerosis. Brain. 1991 Apr;114(Pt 2):937–950. [PubMed]
  • Carton H, Vlietinck R, Debruyne J, De Keyser J, D'Hooghe MB, Loos R, Medaer R, Truyen L, Yee IM, Sadovnick AD. Risks of multiple sclerosis in relatives of patients in Flanders, Belgium. J Neurol Neurosurg Psychiatry. 1997 Apr;62(4):329–333. [PMC free article] [PubMed]
  • Chataway J, Feakes R, Coraddu F, Gray J, Deans J, Fraser M, Robertson N, Broadley S, Jones H, Clayton D, et al. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen. Brain. 1998 Oct;121(Pt 10):1869–1887. [PubMed]
  • Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 1998 Jul 30;339(5):285–291. [PubMed]
  • Coraddu F, Reyes-Yanez MP, Parra A, Gray J, Smith SI, Taylor CJ, Compston DA. HLA associations with multiple sclerosis in the Canary Islands. J Neuroimmunol. 1998 Jul 1;87(1-2):130–135. [PubMed]
  • Coraddu F, Sawcer S, Feakes R, Chataway J, Broadley S, Jones HB, Clayton D, Gray J, Smith S, Taylor C, et al. HLA typing in the United Kingdom multiple sclerosis genome screen. Neurogenetics. 1998 Dec;2(1):24–33. [PubMed]
  • Dean G. Annual incidence, prevalence, and mortality of multiple sclerosis in white South-African-born and in white immigrants to South Africa. Br Med J. 1967 Jun 17;2(5554):724–730. [PMC free article] [PubMed]
  • de la Concha EG, Arroyo R, Crusius JB, Campillo JA, Martin C, Varela de Seijas E, Peña AS, Clavería LE, Fernandez-Arquero M. Combined effect of HLA-DRB1*1501 and interleukin-1 receptor antagonist gene allele 2 in susceptibility to relapsing/remitting multiple sclerosis. J Neuroimmunol. 1997 Dec;80(1-2):172–178. [PubMed]
  • Droogan AG, Kirk CW, Hawkins SA, McMillan SA, Nevin NC, Graham CA. T-cell receptor alpha, beta, gamma, and delta chain gene microsatellites show no association with multiple sclerosis. Neurology. 1996 Oct;47(4):1049–1053. [PubMed]
  • Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature. 1995 Sep 14;377(6545):150–151. [PubMed]
  • Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C, Armstrong H, Cousin K, Bell RB, Hader W, et al. A full genome search in multiple sclerosis. Nat Genet. 1996 Aug;13(4):472–476. [PubMed]
  • Elian M, Dean G. Multiple sclerosis among the United Kingdom-born children of immigrants from the West Indies. J Neurol Neurosurg Psychiatry. 1987 Mar;50(3):327–332. [PMC free article] [PubMed]
  • Feakes R, Sawcer S, Chataway J, Coraddu F, Broadley S, Gray J, Jones HB, Clayton D, Goodfellow PN, Compston A. Exploring the dense mapping of a region of potential linkage in complex disease: an example in multiple sclerosis. Genet Epidemiol. 1999;17(1):51–63. [PubMed]
  • Granieri E, Casetta I. Selected reviews common childhood and adolescent infections and multiple sclerosis. Neurology. 1997 Aug;49(2 Suppl 2):S42–S54. [PubMed]
  • Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D, McDonald WI, Compston DA. Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain. 1992 Aug;115(Pt 4):979–989. [PubMed]
  • He B, Yang B, Lundahl J, Fredrikson S, Hillert J. The myelin basic protein gene in multiple sclerosis: identification of discrete alleles of a 1.3 kb tetranucleotide repeat sequence. Acta Neurol Scand. 1998 Jan;97(1):46–51. [PubMed]
  • He B, Xu C, Yang B, Landtblom AM, Fredrikson S, Hillert J. Linkage and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis. J Neuroimmunol. 1998 Jun 1;86(1):13–19. [PubMed]
  • Kahana E, Zilber N, Abramson JH, Biton V, Leibowitz Y, Abramsky O. Multiple sclerosis: genetic versus environmental aetiology: epidemiology in Israel updated. J Neurol. 1994 Mar;241(5):341–346. [PubMed]
  • Kalman B, Lublin FD, Alder H. Mitochondrial DNA mutations in multiple sclerosis. Mult Scler. 1995 Apr;1(1):32–36. [PubMed]
  • Kellar-Wood H, Robertson N, Govan GG, Compston DA, Harding AE. Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol. 1994 Jul;36(1):109–112. [PubMed]
  • Kuokkanen S, Gschwend M, Rioux JD, Daly MJ, Terwilliger JD, Tienari PJ, Wikström J, Palo J, Stein LD, Hudson TJ, et al. Genomewide scan of multiple sclerosis in Finnish multiplex families. Am J Hum Genet. 1997 Dec;61(6):1379–1387. [PMC free article] [PubMed]
  • Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Part one. Acta Neurol Scand. 1975 Feb;51(2):110–136. [PubMed]
  • Kurtzke JF. Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev. 1993 Oct;6(4):382–427. [PMC free article] [PubMed]
  • Kurtzke JF, Gudmundsson KR, Bergmann S. Multiple sclerosis in Iceland: 1. Evidence of a postwar epidemic. Neurology. 1982 Feb;32(2):143–150. [PubMed]
  • La Mantia L, Illeni MT, Milanese C, Salmaggi A, Eoli M, Pellegris G, Nespolo A. HLA and multiple sclerosis in Italy: a review of the literature. J Neurol. 1990 Nov;237(7):441–444. [PubMed]
  • Ligers A, He B, Fogdell-Hahn A, Olerup O, Hillert J. No linkage or association of a VNTR marker in the junction region of the immunoglobulin heavy chain genes in multiple sclerosis. Eur J Immunogenet. 1997 Aug;24(4):259–264. [PubMed]
  • Marrosu MG, Muntoni F, Murru MR, Costa G, Pischedda MP, Pirastu M, Sotgiu S, Rosati G, Cianchetti C. HLA-DQB1 genotype in Sardinian multiple sclerosis: evidence for a key role of DQB1 *0201 and *0302 alleles. Neurology. 1992 Apr;42(4):883–886. [PubMed]
  • Martyn CN, Cruddas M, Compston DA. Symptomatic Epstein-Barr virus infection and multiple sclerosis. J Neurol Neurosurg Psychiatry. 1993 Feb;56(2):167–168. [PMC free article] [PubMed]
  • Mumford CJ, Wood NW, Kellar-Wood H, Thorpe JW, Miller DH, Compston DA. The British Isles survey of multiple sclerosis in twins. Neurology. 1994 Jan;44(1):11–15. [PubMed]
  • Mycko MP, Kwinkowski M, Tronczynska E, Szymanska B, Selmaj KW. Multiple sclerosis: the increased frequency of the ICAM-1 exon 6 gene point mutation genetic type K469. Ann Neurol. 1998 Jul;44(1):70–75. [PubMed]
  • Nellemann LJ, Frederiksen J, Morling N. PCR typing of two short tandem repeat (STR) structures upstreams of the human myelin basic protein (MBP) gene; the genetic susceptibility in multiple sclerosis and monosymptomatic idiopathic optic neuritis in Danes. Mult Scler. 1995 Nov;1(3):186–189. [PubMed]
  • Nishimura M, Obayashi H, Ohta M, Uchiyama T, Hao Q, Saida T. No association of the 11778 mitochondrial DNA mutation and multiple sclerosis in Japan. Neurology. 1995 Jul;45(7):1333–1334. [PubMed]
  • Olerup O, Hillert J. HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antigens. 1991 Jul;38(1):1–15. [PubMed]
  • Operskalski EA, Visscher BR, Malmgren RM, Detels R. A case-control study of multiple sclerosis. Neurology. 1989 Jun;39(6):825–829. [PubMed]
  • Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. 1995 Apr;118(Pt 2):319–337. [PubMed]
  • Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990 Feb;46(2):222–228. [PMC free article] [PubMed]
  • Robertson NP, Clayton D, Fraser M, Deans J, Compston DA. Clinical concordance in sibling pairs with multiple sclerosis. Neurology. 1996 Aug;47(2):347–352. [PubMed]
  • Robertson NP, Fraser M, Deans J, Clayton D, Walker N, Compston DA. Age-adjusted recurrence risks for relatives of patients with multiple sclerosis. Brain. 1996 Apr;119(Pt 2):449–455. [PubMed]
  • Rodriguez D, Della Gaspera B, Zalc B, Hauw JJ, Fontaine B, Edan G, Clanet M, Dautigny A, Pham-Dinh D. Identification of a Val 145 Ile substitution in the human myelin oligodendrocyte glycoprotein: lack of association with multiple sclerosis. The Réseau de Recherche Clinique INSERM sur la Susceptibilité Génétique à la Sclérose en Plaques. Mult Scler. 1997 Dec;3(6):377–381. [PubMed]
  • Runmarker B, Andersen O. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain. 1995 Feb;118(Pt 1):253–261. [PubMed]
  • Sadovnick AD, Baird PA, Ward RH. Multiple sclerosis: updated risks for relatives. Am J Med Genet. 1988 Mar;29(3):533–541. [PubMed]
  • Sadovnick AD, Armstrong H, Rice GP, Bulman D, Hashimoto L, Paty DW, Hashimoto SA, Warren S, Hader W, Murray TJ, et al. A population-based study of multiple sclerosis in twins: update. Ann Neurol. 1993 Mar;33(3):281–285. [PubMed]
  • Sadovnick AD, Ebers GC, Dyment DA, Risch NJ. Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group. Lancet. 1996 Jun 22;347(9017):1728–1730. [PubMed]
  • Saruhan-Direskeneli G, Esin S, Baykan-Kurt B, Ornek I, Vaughan R, Eraksoy M. HLA-DR and -DQ associations with multiple sclerosis in Turkey. Hum Immunol. 1997 Jun;55(1):59–65. [PubMed]
  • Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J, Robertson N, Clayton D, Goodfellow PN, Compston A. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nat Genet. 1996 Aug;13(4):464–468. [PubMed]
  • Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet. 1985 Jun 8;1(8441):1313–1315. [PubMed]
  • Sibley WA, Bamford CR, Clark K, Smith MS, Laguna JF. A prospective study of physical trauma and multiple sclerosis. J Neurol Neurosurg Psychiatry. 1991 Jul;54(7):584–589. [PMC free article] [PubMed]
  • Siva A, Radhakrishnan K, Kurland LT, O'Brien PC, Swanson JW, Rodriguez M. Trauma and multiple sclerosis: a population-based cohort study from Olmsted County, Minnesota. Neurology. 1993 Oct;43(10):1878–1882. [PubMed]
  • Thompson RJ, Mason CR, Douglas AJ, Hinks LJ, Dwarswaard A, Price SE. Analysis of polymorphisms of the 2',3'-cyclic nucleotide-3'-phosphodiesterase gene in patients with multiple sclerosis. Mult Scler. 1996 Dec;2(5):215–221. [PubMed]
  • Tienari PJ, Wikström J, Sajantila A, Palo J, Peltonen L. Genetic susceptibility to multiple sclerosis linked to myelin basic protein gene. Lancet. 1992 Oct 24;340(8826):987–991. [PubMed]
  • Tienari PJ, Kuokkanen S, Pastinen T, Wikström J, Sajantila A, Sandberg-Wollheim M, Palo J, Peltonen L. Golli-MBP gene in multiple sclerosis susceptibility. J Neuroimmunol. 1998 Jan;81(1-2):158–167. [PubMed]
  • Vandenbroeck K, Martino G, Marrosu M, Consiglio A, Zaffaroni M, Vaccargiu S, Franciotta D, Ruggeri M, Comi G, Grimaldi LM. Occurrence and clinical relevance of an interleukin-4 gene polymorphism in patients with multiple sclerosis. J Neuroimmunol. 1997 Jun;76(1-2):189–192. [PubMed]
  • Wansen K, Pastinen T, Kuokkanen S, Wikström J, Palo J, Peltonen L, Tienari PJ. Immune system genes in multiple sclerosis: genetic association and linkage analyses on TCR beta, IGH, IFN-gamma and IL-1ra/IL-1 beta loci. J Neuroimmunol. 1997 Oct;79(1):29–36. [PubMed]
  • 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 Feb-Mar;7(2):110–116. [PubMed]

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