2019
Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
Patsopoulos N, Baranzini S, Santaniello A, Shoostari P, Cotsapas C, Wong G, Beecham A, James T, Replogle J, Vlachos I, McCabe C, Pers T, Brandes A, White C, Keenan B, Cimpean M, Winn P, Panteliadis I, Robbins A, Andlauer T, Zarzycki O, Dubois B, Goris A, Søndergaard H, Sellebjerg F, Sorensen P, Ullum H, Thørner L, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusic S, Berthele A, Pongratz V, Buck D, Gasperi C, Graetz C, Grummel V, Hemmer B, Hoshi M, Knier B, Korn T, Lill C, Luessi F, Mühlau M, Zipp F, Dardiotis E, Agliardi C, Amoroso A, Barizzone N, Benedetti M, Bernardinelli L, Cavalla P, Clarelli F, Comi G, Cusi D, Esposito F, Ferrè L, Galimberti D, Guaschino C, Leone M, Martinelli V, Moiola L, Salvetti M, Sorosina M, Vecchio D, Zauli A, Santoro S, Mancini N, Zuccalà M, Mescheriakova J, van Duijn C, Bos S, Celius E, Spurkland A, Comabella M, Montalban X, Alfredsson L, Bomfim I, Gomez-Cabrero D, Hillert J, Jagodic M, Lindén M, Piehl F, Jelčić I, Martin R, Sospedra M, Baker A, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Molyneux P, Neville M, Thorpe J, Bradshaw E, Caillier S, Calabresi P, Cree B, Cross A, Davis M, de Bakker P, Delgado S, Dembele M, Edwards K, Fitzgerald K, Frohlich I, Gourraud P, Haines J, Hakonarson H, Kimbrough D, Isobe N, Konidari I, Lathi E, Lee M, Li T, An D, Zimmer A, Madireddy L, Manrique C, Mitrovic M, Olah M, Patrick E, Pericak-Vance M, Piccio L, Schaefer C, Weiner H, Lage K, Compston A, Hafler D, Harbo H, Hauser S, Stewart G, D’Alfonso S, Hadjigeorgiou G, Taylor B, Barcellos L, Booth D, Hintzen R, Kockum I, Martinelli-Boneschi F, McCauley J, Oksenberg J, Oturai A, Sawcer S, Ivinson A, Olsson T, De Jager P. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 2019, 365 PMID: 31604244, PMCID: PMC7241648, DOI: 10.1126/science.aav7188.Peer-Reviewed Original ResearchMeSH KeywordsCase-Control StudiesCell Cycle ProteinsChromosome MappingChromosomes, Human, XGene FrequencyGenetic LociGenome-Wide Association StudyGenomicsGTPase-Activating ProteinsHumansInheritance PatternsMajor Histocompatibility ComplexMicrogliaMultiple SclerosisPolymorphism, Single NucleotideQuantitative Trait LociRNA-SeqTranscriptomeConceptsMajor histocompatibility complexMultiple sclerosisImmune cellsBrain-resident immune cellsPeripheral immune cellsPeripheral immune responseCentral nervous systemExtended major histocompatibility complexAutoimmune processControl subjectsHuman microgliaImmune responseNervous systemImmune systemHistocompatibility complexPutative susceptibility genesMicrogliaX variantGenetic architectureSusceptibility genesGenomic mapGenetic dataExpression profilesM geneSusceptibility variantsLatent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients
James JA, Chen H, Young KA, Bemis EA, Seifert J, Bourn RL, Deane KD, Demoruelle MK, Feser M, O'Dell JR, Weisman MH, Keating RM, Gaffney PM, Kelly JA, Langefeld CD, Harley JB, Robinson W, Hafler DA, O'Connor KC, Buckner J, Guthridge JM, Norris JM, Holers VM. Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients. EBioMedicine 2019, 42: 76-85. PMID: 30952617, PMCID: PMC6491794, DOI: 10.1016/j.ebiom.2019.03.063.Peer-Reviewed Original ResearchConceptsSystemic lupus erythematosusFirst-degree relativesGenetic risk scoreRA patientsRheumatoid arthritisSLE patientsT1D patientsAutoantibody-positive systemic lupus erythematosusRisk first-degree relativesOrgan-specific autoimmune diseasesType 1 diabetes patientsAutoimmune disease preventionAnti-tissue transglutaminaseDisease-associated autoantibodiesDisease prevention studiesUnaffected first-degree relativesCross-sectional studyLatent autoimmunityLupus erythematosusAutoimmune diseasesDiabetes patientsPrevention StudyRisk scoreAutoimmunityPreclinical period
2011
Genome‐wide meta‐analysis identifies novel multiple sclerosis susceptibility loci
Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J, Sandbrink R, Pohl C, Edan G, Kappos L, Miller D, Montalbán J, Polman C, Freedman M, Hartung H, Arnason B, Comi G, Cook S, Filippi M, Goodin D, Jeffery D, O'Connor P, Ebers G, Langdon D, Reder A, Traboulsee A, Zipp F, Schimrigk S, Hillert J, Bahlo M, Booth D, Broadley S, Brown M, Browning B, Browning S, Butzkueven H, Carroll W, Chapman C, Foote S, Griffiths L, Kermode A, Kilpatrick T, Lechner-Scott J, Marriott M, Mason D, Moscato P, Heard R, Pender M, Perreau V, Perera D, Rubio J, Scott R, Slee M, Stankovich J, Stewart G, Taylor B, Tubridy N, Willoughby E, Wiley J, Matthews P, Boneschi F, Compston A, Haines J, Hauser S, McCauley J, Ivinson A, Oksenberg J, Pericak-Vance M, Sawcer S, De Jager P, Hafler D, de Bakker P. Genome‐wide meta‐analysis identifies novel multiple sclerosis susceptibility loci. Annals Of Neurology 2011, 70: 897-912. PMID: 22190364, PMCID: PMC3247076, DOI: 10.1002/ana.22609.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesSingle nucleotide polymorphismsSusceptibility lociHapMap Phase IIUnique single nucleotide polymorphismsGene discovery effortsNew susceptibility lociStrongest cis effectsMS genome-wide association studiesQuantitative trait analysisFlanking genesGenetic architectureRNA expression dataMultiple sclerosis susceptibility lociIntergenic regionSecond intronNew lociNovel susceptibility allelesAdditional lociTrait analysisAssociation studiesExpression dataChromosome 2p21LociFunctional consequencesIncreased Frequencies of Myelin Oligodendrocyte Glycoprotein/MHC Class II-Binding CD4 Cells in Patients with Multiple Sclerosis
Raddassi K, Kent SC, Yang J, Bourcier K, Bradshaw EM, Seyfert-Margolis V, Nepom GT, Kwok WW, Hafler DA. Increased Frequencies of Myelin Oligodendrocyte Glycoprotein/MHC Class II-Binding CD4 Cells in Patients with Multiple Sclerosis. The Journal Of Immunology 2011, 187: 1039-1046. PMID: 21653833, PMCID: PMC3131477, DOI: 10.4049/jimmunol.1001543.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAmino Acid SubstitutionCD4 Lymphocyte CountCD4-Positive T-LymphocytesCell CommunicationCell Line, TransformedCells, CulturedEpitopes, T-LymphocyteFemaleGene FrequencyHLA-DR AntigensHLA-DRB1 ChainsHumansImmunophenotypingMaleMiddle AgedMultiple SclerosisMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinPeptide FragmentsProtein BindingProtein MultimerizationConceptsMyelin-reactive T cellsMultiple sclerosisT cell clonesT cellsHealthy controlsMOG-reactive T cellsAutoantigen-specific T cellsCell clonesStimulation of PMBCsClass II tetramersPathogenic immune cellsReactive T cellsSpecific T cellsMyelin oligodendrocyte glycoproteinHLA class IIBlood of subjectsT-cell cloning techniqueMOG peptidesShort-term cultureCD4 cellsMS subjectsAutoimmune diseasesPeripheral bloodControl subjectsOligodendrocyte glycoprotein
2010
HLA B*44
Healy BC, Liguori M, Tran D, Chitnis T, Glanz B, Wolfish C, Gauthier S, Buckle G, Houtchens M, Stazzone L, Khoury S, Hartzmann R, Fernandez-Vina M, Hafler DA, Weiner HL, Guttmann CR, De Jager PL. HLA B*44. Neurology 2010, 75: 634-640. PMID: 20713950, PMCID: PMC2931768, DOI: 10.1212/wnl.0b013e3181ed9c9c.Peer-Reviewed Original ResearchMeSH KeywordsAdultChi-Square DistributionDisease ProgressionFemaleGene FrequencyGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHLA AntigensHLA-A AntigensHLA-B AntigensHLA-B44 AntigenHLA-C AntigensHumansLogistic ModelsMagnetic Resonance ImagingMaleMiddle AgedMultiple SclerosisOutcome Assessment, Health CareRadiographySeverity of Illness IndexConceptsDisease courseT2 hyperintense lesion volumeBetter radiologic outcomesHyperintense lesion volumeT2 hyperintense lesionsBrain parenchymal fractionBone Marrow Donor RegistryMHC class IMarrow Donor RegistryMS susceptibility lociClass I MHC lociRadiologic outcomesHyperintense lesionsParenchymal fractionLesion volumeOutcome measuresClinical measuresMS susceptibilityBrain volumeHLAProtective allelesLogistic regressionPatient samplesDonor registryRisk allelesGenetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility
Zuvich RL, McCauley JL, Oksenberg JR, Sawcer SJ, De Jager PL, International Multiple Sclerosis Genetics Consortium, Aubin C, Cross AH, Piccio L, Aggarwal NT, Evans D, Hafler DA, Compston A, Hauser SL, Pericak-Vance MA, Haines JL. Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility. Human Genetics 2010, 127: 525-535. PMID: 20112030, PMCID: PMC2854871, DOI: 10.1007/s00439-010-0789-4.Peer-Reviewed Original ResearchConceptsSingle nucleotide polymorphismsGene regionCase-control data setsPutative functional relationshipsNovel gene regionsIndependent case-control data setDense SNP mapReceptor alpha-chain geneIllumina Infinium BeadChipExperiment-wise significanceNovel associationsAlpha chain geneGenetic architectureComplex traitsStrong genetic componentGenetic variationSNP mapInfinium BeadChipAffordable genotypingBiological pathwaysGenesGenetic componentChain geneTYK2 geneNumerous family studies
2008
Integrating risk factors
De Jager PL, Simon KC, Munger KL, Rioux JD, Hafler DA, Ascherio A. Integrating risk factors. Neurology 2008, 70: 1113-1118. PMID: 18272866, DOI: 10.1212/01.wnl.0000294325.63006.f8.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodiesBiomarkersCase-Control StudiesComorbidityEpstein-Barr Virus InfectionsEpstein-Barr Virus Nuclear AntigensFemaleGene FrequencyGenetic Predisposition to DiseaseGenotypeHerpesvirus 4, HumanHeterozygoteHLA-DR AntigensHLA-DRB1 ChainsHumansMiddle AgedMultiple SclerosisRisk FactorsConceptsMultiple sclerosisHuman leukocyte antigenAntibody titersRisk factorsDR15 alleleEpstein-Barr virus (EBV) antibody titersAge-matched healthy womenRisk of MSEpstein-Barr virus nuclear antigen 1Independent risk factorVirus antibody titersCase-control studyNuclear antigen 1Healthy womenMS riskLeukocyte antigenRelative riskGenetic susceptibilityAntigen 1TitersWomenSclerosisRiskDR15Association
2007
The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases
De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, Belaiche J, Vermeire S, Farwell L, Goris A, Libioulle C, Jani N, Dassopoulos T, Bromfield GP, Dubois B, Cho JH, Brant SR, Duerr RH, Yang H, Rotter JI, Silverberg MS, Steinhart AH, Daly MJ, Podolsky DK, Louis E, Hafler DA, Rioux JD. The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes & Immunity 2007, 8: 387-397. PMID: 17538633, DOI: 10.1038/sj.gene.6364398.Peer-Reviewed Original ResearchConceptsInflammatory bowel diseaseCases of IBDRisk of IBDToll-like receptorsBowel diseaseIBD risk allelesUlcerative colitisCrohn's diseaseTLR4 pathwayIBD pathophysiologyIntestinal floraTLR pathwayTLR4 allelesHost defenseReceptor pathwayRisk allelesTLR genesDiseaseTLR4Modest effectHost/pathogen interactionsTIRAPAssociationReplication studyRisk
2005
Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis
De Jager PL, Sawcer S, Waliszewska A, Farwell L, Wild G, Cohen A, Langelier D, Bitton A, Compston A, Hafler DA, Rioux JD. Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis. European Journal Of Human Genetics 2005, 14: 317-321. PMID: 16391555, DOI: 10.1038/sj.ejhg.5201548.Peer-Reviewed Original ResearchMeSH KeywordsAllelesCanadaCase-Control StudiesCrohn DiseaseGene FrequencyGenetic Predisposition to DiseaseGenotypeHumansInflammationModels, StatisticalMultiple SclerosisOdds RatioPolymorphism, GeneticProtein Tyrosine Phosphatase, Non-Receptor Type 1Protein Tyrosine Phosphatase, Non-Receptor Type 22Protein Tyrosine PhosphatasesRiskUnited KingdomConceptsSystemic lupus erythematosusCases of CDCrohn's diseaseMultiple sclerosisPTPN22 620W alleleAutoimmune thyroiditisRheumatoid arthritisInflammatory diseasesEvidence of associationCases of MSProtein tyrosine phosphatase PTPN22Chronic inflammatory diseaseType 1 diabetesTyrosine phosphatase PTPN22PTPN22 alleleLupus erythematosusPooled analysisControl subjectsModest odds ratiosOdds ratioDiseaseRisk allelesPhosphatase PTPN22SclerosisPossible role
2004
Methods for High-Density Admixture Mapping of Disease Genes
Patterson N, Hattangadi N, Lane B, Lohmueller KE, Hafler DA, Oksenberg JR, Hauser SL, Smith MW, O’Brien S, Altshuler D, Daly MJ, Reich D. Methods for High-Density Admixture Mapping of Disease Genes. American Journal Of Human Genetics 2004, 74: 979-1000. PMID: 15088269, PMCID: PMC1181990, DOI: 10.1086/420871.Peer-Reviewed Original ResearchA High-Density Admixture Map for Disease Gene Discovery in African Americans
Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A, Kessing BD, Malasky MJ, Scafe C, Le E, De Jager PL, Mignault AA, Yi Z, de Thé G, Essex M, Sankalé J, Moore JH, Poku K, Phair JP, Goedert JJ, Vlahov D, Williams SM, Tishkoff SA, Winkler CA, De La Vega FM, Woodage T, Sninsky JJ, Hafler DA, Altshuler D, Gilbert DA, O’Brien S, Reich D. A High-Density Admixture Map for Disease Gene Discovery in African Americans. American Journal Of Human Genetics 2004, 74: 1001-1013. PMID: 15088270, PMCID: PMC1181963, DOI: 10.1086/420856.Peer-Reviewed Original Research
2003
Activated CD8+ T cells in secondary progressive MS secrete lymphotoxin
Buckle GJ, Höllsberg P, Hafler DA. Activated CD8+ T cells in secondary progressive MS secrete lymphotoxin. Neurology 2003, 60: 702-705. PMID: 12601116, DOI: 10.1212/01.wnl.0000048204.89346.30.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodiesCD3 ComplexCD8-Positive T-LymphocytesCell DivisionCell SeparationCells, CulturedCytokinesFemaleFlow CytometryGene FrequencyHumansLymphotoxin-alphaMaleMiddle AgedMultiple Sclerosis, Chronic ProgressiveMultiple Sclerosis, Relapsing-RemittingPolymorphism, Single NucleotideReference ValuesConceptsT cellsNormal controlsSecondary progressive MSCytokine secretion profileFunctional activation statesLymphotoxin secretionProgressive MSActivated CD8Cytokine secretionSecretion profileCytokine genesCD8SecretionSignificant differencesPatientsSignificant increaseActivation stateSingle nucleotide polymorphism analysisPolymorphism analysisNucleotide polymorphism analysisCells