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REVIEW ARTICLEHanne F Harbo,MD, PhDis Professor of Neurology at OsloUniversity Hospital, Oslo, Norway.She is the leader of the Oslo MSGenetics Group and theNorwegian lead member inNordic MS Genetic Network andIMSGC, and was the leader of theEFNS scientist panel of neurogeneticsfrom 2007-2010. Her focusof interest is MS treatment andresearch, in particular immunogeneticstudies of MS.Maria Ban, PhDis a postdoctoral researcher in theDepartment of ClinicalNeurosciences, CambridgeUniversity, UK. Her researchinterest is in identifying thegenetic factors involved insusceptibility to multiplesclerosis.Correspondence to:Hanne F HarboProfessor, dr. med (MD, PhD)Department of Neurology,Oslo University Hospital, Ullevåland University of Oslo0407 Oslo, NorwayEmail: h.f.harbo@medisin.uio.noAcknowledgement:We thank all our collaboratorsworld-wide in the IMSGC andWTCCC. Stephen Sawcer iswarmly thanked for comments tothis manuscript.Disclosures:HF Harbo has received research grantsfrom the Norwegian Research Council,South-East Regional Norwegian HealthAuthorities, Oslo University Hospital,Norwegian and Oslo MS association,Odd Fellow MS society, diverse otherNorwegian research funds, Sanofi-Aventis, Novartis, Biogen-Idec, BayerSchering, as well as Wellcome Trust, UKthrough the IMSGC grant for genotypingof Norwegian samples in theIMSGC-WTCCC MS GWAS.Maria Ban is supported by a grant fromthe Wellcome Trust.From GWAS toMolecules in MSMultiple sclerosis (MS) is one of the mostfrequent causes of neurological disability inyoung adults in western countries. Despiteextensive efforts, little is known about events thattrigger the disease or factors that control its highlyvariable course and severity.Given its unpredictable nature, alongside theaccumulation of significant disability in a largeproportion of patients, MS is a feared disease, oftenleading to a severe impact on patients and theirfamilies as well as a large cost for society. Theestablished immune modulation MS therapies areonly indicated for the relapsing remitting forms ofMS and are often only partly effective, some withserious side effects. The development of moresuccessful treatments is limited by our poor understandingof pathogenesis and disease mechanisms.Through genetic and molecular studies ofMS, guidance to ‘personalised medicine’ andestablishment of new therapies can hopefully beachieved.Familial clustering is a firmly established featurein MS, with 15-20% of affected individuals having afamily history of the disease, epidemiologicalstudies showing this is primarily a result of sharedgenes rather than a shared environment. 1 The importanceof genetic factors in determining susceptibilityto the disease prompted efforts towards identifyingresponsible genes in the expectation that thisknowledge will provide invaluable informationabout pathogenesis and inform future research intoeffective treatments.Candidate gene studies identified the importanceof HLA genes in MSEarly genetic research efforts quickly establishedassociation with the human leukocyte antigen(HLA) region in the major histocompatibilitycomplex (MHC) on chromosome 6p21. 2Subsequent research efforts have refined this associationand confirmed that in virtually every populationtested, risk is primarily determined by the classII allele HLA-DRB1*15:01. 3 Carriers of this risk alleletypically have a three-fold increased risk of developingMS, making this the largest genetic factorpredisposing an individual to MS yet identified.Considerable progress in fine mapping anddissecting this important signal has providedgrowing evidence supporting the involvement ofgenes within the class I region with MS, independentof the 15:01 association. 4 Much work still needs to beundertaken to completely understand the role ofthis complex region in the development of MS.In the years following the HLA discovery, despitethe heritable nature of susceptibility to MS, candidategene studies made remarkably little progress inidentifying the genes involved in MS. The invariableuse of inadequate sample sizes coupled with thelimited probability that a relevant gene might beselected for study have been prominent amongstthe reasons for the limited success of this approach.Genome screening identified the firstnon-HLA gene associations in MSAs such the momentum shifted towards screeningthe genome, an advantageous method as no priorknowledge of the pathogenesis of disease isrequired as genetic variants are screenedthroughout the genome in the hope that they will becorrelated with the disease causing allele. The firstgenome screens were performed by linkage analysisgenotyping microsatellite markers in affected sibpairfamilies in the mid-1990s in the UK 5 , US 6 andCanadian 7 population and have since beencompleted in several other populations.Disappointingly no region of genome wide significancewas identified in any study and little overlapin the results between studies was found. In 2005, adefinitive linkage screen was completed by theInternational Multiple Sclerosis GeneticsConsortium (IMSGC), by whom 4506 singlenucleotide polymorphisms (SNPs) were typed in730 multiplex families. 8 While the only region toreach genome wide significance was the alreadyestablished HLA region, this linkage study did establishthat outside the HLA region, common susceptibilityalleles (frequency >10%) are unlikely toincrease the risk of disease by a factor of more thantwo and therefore association screening is a morepowerful method to establish these small geneticeffects in MS.It was only as the understanding of the nature andextent of human genetic variation increased and thetechnology to screen hundreds of thousands ofsingle nucleotide polymorphisms (SNPs) in thehuman genome in a cost and time efficient mannerbecome available, that the ability to completegenome-wide association screens (GWAS) wasmade possible. The first high-density genome wideassociation screen in MS was published in 2007. 9Close to 1000 trio families (an affected individualand both of their parents) were screened for over300,000 SNPs and implicated the IL7RA and IL2RAgenes in MS susceptibility, which was successfullyreplicated and confirmed in other populations. 10Since then more than 10 GWAS and meta-analysisstudies have been completed and alongside replicationstudies have confirmed a growing list of genesinvolved in MS susceptibility (see Figure 1). 9 20 Theseare the first genuine associations to be identified inmultiple sclerosis since the long established associationwithin the HLA region. As indicated by the MSlinkage studies, 9 no other MS loci have been identifiedwith a higher risk than the HLA region, reflectedin odds ratios typically around 1.2 for the now establishednon-HLA MS risk loci (Figure 1).Interestingly these associations have uncovered agrowing overlap in susceptibility loci between MS14 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011