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 variants
2015
Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli
Housley WJ, Fernandez SD, Vera K, Murikinati SR, Grutzendler J, Cuerdon N, Glick L, De Jager PL, Mitrovic M, Cotsapas C, Hafler DA. Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli. Science Translational Medicine 2015, 7: 291ra93. PMID: 26062845, PMCID: PMC4574294, DOI: 10.1126/scitranslmed.aaa9223.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAllelesAutoimmunityCase-Control StudiesCD4-Positive T-LymphocytesCell NucleusCytokinesFemaleGenetic Predisposition to DiseaseHumansInflammationMaleMiddle AgedMultiple SclerosisNF-kappa BPolymorphism, Single NucleotideProtein TransportReceptors, Tumor Necrosis Factor, Type IRisk FactorsSex CharacteristicsSignal TransductionTime FactorsTumor Necrosis Factor-alphaConceptsB-cell leukemia 3Multiple sclerosisNegative regulatorInflammatory stimuliGenetic variantsWide association studyDisease susceptibility variantsNaïve CD4 T cellsRapid genetic screeningCD4 T cellsActivation of p65Transcription factor nuclear factor κBExpression of NFκBNuclear factor κBApoptosis 1Cellular inhibitorGG risk genotypeDegradation of inhibitorCentral regulatorAssociation studiesCytokine blockadeUlcerative colitisAutoimmune diseasesTumor necrosisSusceptibility variants
2014
Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes
Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM, Feng T, Lee M, Asinovski N, Frohlich I, Imboywa S, Von Korff A, Okada Y, Patsopoulos NA, Davis S, McCabe C, Paik HI, Srivastava GP, Raychaudhuri S, Hafler DA, Koller D, Regev A, Hacohen N, Mathis D, Benoist C, Stranger BE, De Jager PL. Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes. Science 2014, 344: 519-523. PMID: 24786080, PMCID: PMC4910825, DOI: 10.1126/science.1249547.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAllelesAlzheimer DiseaseAutoimmune DiseasesAutoimmunityCD4-Positive T-LymphocytesEthnicityGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansImmunity, InnateMonocytesMultiple SclerosisNeurodegenerative DiseasesParkinson DiseasePolymorphism, Single NucleotideQuantitative Trait LociRheumatic FeverTranscriptomeConceptsSpecific immune cell typesHuman immune functionImmune cell typesMulti-ethnic cohortCell-autonomous effectsAutoimmune diseasesT cellsImmune functionParkinson's diseaseHealthy individualsInnate immunityRisk allelesDiseaseExpression quantitative trait loci (eQTL) studiesQuantitative trait loci studiesSusceptibility allelesPutative functional assignmentsCausal regulatory variantsDisease-associated lociDisease susceptibility variantsCell typesSusceptibility variantsTrans-eQTLsFunctional assignmentRegulatory variants
2013
Network-Based Multiple Sclerosis Pathway Analysis with GWAS Data from 15,000 Cases and 30,000 Controls
Consortium I, Baranzini S, Khankhanian P, Patsopoulos N, Li M, Stankovich J, Cotsapas C, Søndergaard H, Ban M, Barizzone N, Bergamaschi L, Booth D, Buck D, Cavalla P, Celius E, Comabella M, Comi G, Compston A, Cournu-Rebeix I, D’alfonso S, Damotte V, Din L, Dubois B, Elovaara I, Esposito F, Fontaine B, Franke A, Goris A, Gourraud P, Graetz C, Guerini F, Guillot-Noel L, Hafler D, Hakonarson H, Hall P, Hamsten A, Harbo H, Hemmer B, Hillert J, Kemppinen A, Kockum I, Koivisto K, Larsson M, Lathrop M, Leone M, Lill C, Macciardi F, Martin R, Martinelli V, Martinelli-Boneschi F, McCauley J, Myhr K, Naldi P, Olsson T, Oturai A, Pericak-Vance M, Perla F, Reunanen M, Saarela J, Saker-Delye S, Salvetti M, Sellebjerg F, Sørensen P, Spurkland A, Stewart G, Taylor B, Tienari P, Winkelmann J, Consortium W, Zipp F, Ivinson A, Haines J, Sawcer S, DeJager P, Hauser S, Oksenberg J. Network-Based Multiple Sclerosis Pathway Analysis with GWAS Data from 15,000 Cases and 30,000 Controls. American Journal Of Human Genetics 2013, 92: 854-865. PMID: 23731539, PMCID: PMC3958952, DOI: 10.1016/j.ajhg.2013.04.019.Peer-Reviewed Original ResearchConceptsPathway analysisNetwork-based pathway analysisGenome-wide association studiesSubnetworks of genesExtended linkage disequilibriumNon-HLA susceptibility lociHigh-confidence candidatesSubsequent genetic studiesComplex traitsSubstantial genetic componentSignificant lociGWAS dataAssociation studiesGene levelGenetic studiesNominal statistical evidenceSusceptibility lociGenesLinkage disequilibriumSusceptibility variantsGenetic componentRelated pathwaysLociHuman leukocyte antigen (HLA) regionPowerful approach
2009
Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases
Rioux J, Goyette P, Vyse T, Hammarström L, Fernando M, Green T, De Jager P, Foisy S, Wang J, de Bakker P, Leslie S, McVean G, Padyukov L, Alfredsson L, Annese V, Hafler D, Pan-Hammarström Q, Matell R, Sawcer S, Compston A, Cree B, Mirel D, Daly M, Behrens T, Klareskog L, Gregersen P, Oksenberg J, Hauser S. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 18680-18685. PMID: 19846760, PMCID: PMC2773992, DOI: 10.1073/pnas.0909307106.Peer-Reviewed Original ResearchConceptsAutoimmune diseasesSystemic lupus erythematosusSelective IgA deficiencyStrong susceptibility locusNon-HLA genesMHC regionLupus erythematosusMyasthenia gravisUlcerative colitisCrohn's diseaseRheumatoid arthritisIgA deficiencyMultiple sclerosisMultiple susceptibility variantsMHC associationsDiseaseAppropriate control samplesPrimary association signalStrong linkage disequilibriumIndependent association signalsHuman MHCSusceptibility variantsSusceptibility lociAssociation signalsMost studies
2007
Allelic variant in CTLA4 alters T cell phosphorylation patterns
Maier LM, Anderson DE, De Jager PL, Wicker LS, Hafler DA. Allelic variant in CTLA4 alters T cell phosphorylation patterns. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 18607-18612. PMID: 18000051, PMCID: PMC2141824, DOI: 10.1073/pnas.0706409104.Peer-Reviewed Original ResearchConceptsT cell antigen receptorAllelic variationMemory T cellsAutoimmune diseasesCell antigen receptorT cell signalingT cellsFunctional effectsDisease susceptibility allelesCell signalingPhosphorylation patternPhosphorylation levelsSusceptibility variantsTCR stimulationAllelic variantsHuman immune cellsAntigen receptorGenesImmune cellsHealthy individualsCTLA4 geneCellsSpecific mAbsCTLA4Disease