Review| Volume 2, ISSUE 3, P156-161, July 2013

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Multiple sclerosis genetics is dead

Published:February 18, 2013DOI:


      This review addresses several areas of contention related to the genetic theory for multiple sclerosis (MS). It is argued (a) that the concept of MS as a ‘complex disease’ has little value, (b) just because a disorder is found in multiple families, it is not necessarily genetically based, (c) although twin studies are claimed to show that MS is ‘30% genetically based’ this concept derives from widely varying data, (d) although genome-wide association studies (GWAS) suggest the presence of several MS related genes this has yet to be proven, (e) monozygotic twins discordant for MS should have a different genetic sequence if the disorder has a genetic basis but data so far suggest this may not be correct and (f) epigenetics or epistasis are contentious topics and may not provide the answer. It is concluded that the role of genetics in MS etiology may be overstated and that attention should now be devoted to environmental causes.


      • The term ‘complex disease’ has no useful meaning and should not be used.
      • Multicase pedigrees do not necessarily have a primary genetic basis.
      • Classic twin studies MS are inconclusive.
      • GWAS have not isolated any mutations for MS, unlike familial parkinsonism.
      • The words ‘epigenetic’ and ‘epistasis’ are speculative processes for MS.
      • The balance of current evidence does not support a major genetic role in MS.


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        • Ascherio A.
        • Munger K.L.
        Environmental risk factors for multiple sclerosis. Part I: the role of infection.
        Annals of Neurology. 2007; 61: 288-299
        • Ascherio A.
        • Munger K.L.
        Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors.
        Annals of Neurology. 2007; 61: 504-513
        • Baranzini S.E.
        • Mudge J.
        • van Velkinburgh J.C.
        • Khankhanian P.
        • Khrebtukova I.
        • Miller N.A.
        • et al.
        Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.
        Nature. 2010; 464: 1351-1356
        • Baranzini S.E.
        • Nickles D.
        Genetics of multiple sclerosis: swimming in an ocean of data.
        Current Opinion in Neurology. 2012; 25: 239-245
        • Blackwell J.M.
        Genetics of host resistance and susceptibility to intramacrophage pathogens: a study of multicase families of tuberculosis, leprosy and leishmaniasis in north-eastern Brazil.
        International Journal for Parasitology. 1998; 28: 21-28
        • Dawodu A
        • Absood G
        • Patel M
        • Agarwal M
        • Ezimokhai M
        • Abdulrazzaq Y
        • et al.
        Biosocial factors affecting vitamin D status of women of childbearing age in the United Arab Emirates.
        Journal of Biosocial Science. 1998; 30: 431-437
        • Disanto G
        • Sandve GK
        • Berlanga-Taylor AJ
        • Ragnedda G
        • Morahan JM
        • Watson CT
        • et al.
        Vitamin D receptor binding, chromatin states and association with multiple sclerosis.
        Human Molecular Genetics. 2012; 21: 3575-3586
        • Dyment D.A.
        • Cader M.Z.
        • Willer C.J.
        • Risch N.
        • Sadovnick A.D.
        • Ebers G.C.
        A multigenerational family with multiple sclerosis.
        Brain. 2002; 125: 1474-1482
        • Gourraud P.A.
        • Harbo H.F.
        • Hauser S.L.
        • Baranzini S.E.
        The genetics of multiple sclerosis: an up-to-date review.
        Immunological Reviews. 2012; 248: 87-103
        • Guzel R.
        • Kozanoglu E.
        • Guler-Uysal F.
        • Soyupak S.
        • Sarpel T.
        Vitamin D status and bone mineral density of veiled and unveiled Turkish women.
        Journal of Women's Health and Gender-Based Medicine. 2001; 10: 765-770
        • Hansen T.
        • Skytthe A.
        • Stenager E.
        • Petersen H.C.
        • Kyvik K.O.
        • Bronnum-Hansen H.
        Risk for multiple sclerosis in dizygotic and monozygotic twins.
        Multiple Sclerosis. 2005; 11: 500-503
        • Hawkes C.H.
        • Macgregor A.J.
        Twin studies and the heritability of MS: a conclusion.
        Multiple Sclerosis. 2009; 15: 661-667
        • Islam T.
        • Gauderman W.J.
        • Cozen W.
        • Hamilton A.S.
        • Burnett M.E.
        • Mack T.M.
        Differential twin concordance for multiple sclerosis by latitude of birthplace.
        Annals of Neurology. 2006; 60: 56-64
        • Jeffery KJ
        • Siddiqui AA
        • Bunce M
        • Lloyd AL
        • Vine AM
        • Witkover AD
        • et al.
        The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection.
        Journal of Immunology. 2000; 165: 7278-7284
      1. LeishGEN Consortium; Wellcome Trust Case Control Consortium 2, Fakiola M, Strange A, Cordell HJ, Miller EN, Pirinen M, Su Z, et al. Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis. Nature Genetics 2013;45(2):208–13.

        • Noble J.A.
        • Erlich H.A.
        Genetics of type 1 diabetes.
        Cold Spring Harbor Perspectives in Medicine. 2012; 2: a007732
        • Ramagopalan SV
        • Dyment DA
        • Cader MZ
        • Morrison KM
        • Disanto G
        • Morahan JM
        • et al.
        Rare variants in the CYP27B1 gene are associated with multiple sclerosis.
        Annals of Neurology. 2011; 70: 881-886
        • Rose A.M.
        • Bell L.C.
        Epistasis and immunity: the role of genetic interactions in autoimmune diseases.
        Immunology. 2012;
        • Sadovnick A.D.
        Genetic background of multiple sclerosis.
        Autoimmunity Reviews. 2012; 11: 163-166
        • Torkildsen O.
        • Knappskog P.M.
        • Nyland H.I.
        • Myhr K.M.
        Vitamin D-dependent rickets as a possible risk factor for multiple sclerosis.
        Archives of Neurology. 2008; 65: 809-811
        • Wexler NS
        • Lorimer J
        • Porter J
        • Gomez F
        • Moskowitz C
        • Shackell E
        • et al.
        Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset.
        Proceedings of the National Academy of Sciences of the United States of America. 2004; 101: 3498-3503
      2. Wikipedia 〈〉, 2012

        • Wondale Y.
        • Shiferaw F.
        • Lulseged S.
        A systematic review of nutritional rickets in Ethiopia: status and prospects.
        Ethiopian Medical Journal. 2005; 43: 203-210
        • Yang H.C.
        • Chang L.C.
        • Liang Y.J.
        • Lin C.H.
        • Wang P.L.
        A genome-wide homozygosity association study identifies runs of homozygosity associated with rheumatoid arthritis in the human major histocompatibility complex.
        PLoS One. 2012; 7: e34840
        • Zhang FR
        • Huang W
        • Chen SM
        • Sun LD
        • Liu H
        • Li Y
        • et al.
        Genomewide association study of leprosy.
        New England Journal of Medicine. 2009; 361: 2609-2618