2024
Genetic mapping across autoimmune diseases reveals shared associations and mechanisms
Lincoln M, Connally N, Axisa P, Gasperi C, Mitrovic M, van Heel D, Wijmenga C, Withoff S, Jonkers I, Padyukov L, Rich S, Graham R, Gaffney P, Langefeld C, Vyse T, Hafler D, Chun S, Sunyaev S, Cotsapas C. Genetic mapping across autoimmune diseases reveals shared associations and mechanisms. Nature Genetics 2024, 56: 838-845. PMID: 38741015, DOI: 10.1038/s41588-024-01732-8.Peer-Reviewed Original ResearchConceptsGenetic mapResolution of genetic mappingExpression quantitative trait lociFine-mapping resolutionQuantitative trait lociGenomic lociTrait lociPolygenic disorderAllelesRisk allelesLociPathogenic mechanismsImmune systemAutoimmune mechanismsAutoimmune diseasesInflammatory diseasesTraitsMechanismDiseaseSample collectionExpression
2023
Common genetic factors among autoimmune diseases
Harroud A, Hafler D. Common genetic factors among autoimmune diseases. Science 2023, 380: 485-490. PMID: 37141355, DOI: 10.1126/science.adg2992.Peer-Reviewed Original ResearchMeSH KeywordsAutoimmune DiseasesGenetic Predisposition to DiseaseGenomeGenome-Wide Association StudyHumansRisk FactorsConceptsGenome-wide association studiesMultimodal genomic dataEvolutionary originDisease geneticsPolygenic basisPrecise geneSelection pressureGenomic dataMolecular consequencesAssociation studiesGenetic studiesFunctional experimentsGenetic effectsRisk variantsCommon genetic factorsAncient populationsCurrent understandingPotential therapeutic implicationsGenetic factorsKey immune cellsGenesGeneticsWidespread sharingImmune cellsValuable insights
2022
A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells
Axisa P, Yoshida T, Lucca L, Kasler H, Lincoln M, Pham G, Del Priore D, Carpier J, Lucas C, Verdin E, Sumida T, Hafler D. A multiple sclerosis–protective coding variant reveals an essential role for HDAC7 in regulatory T cells. Science Translational Medicine 2022, 14: eabl3651. PMID: 36516268, DOI: 10.1126/scitranslmed.abl3651.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesDisease Models, AnimalGenome-Wide Association StudyHistone DeacetylasesHumansMiceMultiple SclerosisT-Lymphocytes, RegulatoryConceptsExperimental autoimmune encephalitisRegulatory T cellsHistone deacetylase 7Multiple sclerosisT cellsMouse modelFunction of Foxp3CD4 T cellsHigher suppressive capacityVivo modelingAutoimmune encephalitisEAE severityImmunosuppressive subsetAutoimmune diseasesImmunomodulatory roleSuppressive capacityImmune cellsDisease onsetDistinct molecular classesSusceptibility lociGenetic susceptibility lociSingle-cell RNA sequencingDisease riskPatient samplesProtective variants
2020
Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans
Nakatsuka N, Patterson N, Patsopoulos NA, Altemose N, Tandon A, Beecham AH, McCauley JL, Isobe N, Hauser S, De Jager PL, Hafler DA, Oksenberg JR, Reich D. Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans. Scientific Reports 2020, 10: 16902. PMID: 33037294, PMCID: PMC7547691, DOI: 10.1038/s41598-020-74035-7.Peer-Reviewed Original Research
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
2018
Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk
Consortium I, Mitrovič M, Patsopoulos N, Beecham A, Dankowski T, Goris A, Dubois B, D’hooghe M, Lemmens R, Van Damme P, Søndergaard H, Sellebjerg F, Sorensen P, Ullum H, Thørner L, Werge T, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusik S, Gourraud P, Andlauer T, Pongratz V, Buck D, Gasperi C, Bayas A, Heesen C, Kümpfel T, Linker R, Paul F, Stangel M, Tackenberg B, Bergh F, Warnke C, Wiendl H, Wildemann B, Zettl U, Ziemann U, Tumani H, Gold R, Grummel V, Hemmer B, Knier B, Lill C, Luessi F, Dardiotis E, Agliardi C, Barizzone N, Mascia E, Bernardinelli L, Comi G, Cusi D, Esposito F, Ferrè L, Comi C, Galimberti D, Leone M, Sorosina M, Mescheriakova J, Hintzen R, van Duijn C, Theunissen C, Bos S, Myhr K, Celius E, Lie B, Spurkland A, Comabella M, Montalban X, Alfredsson L, Stridh P, Hillert J, Jagodic M, Piehl F, Jelčić I, Martin R, Sospedra M, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Neville M, Santaniello A, Caillier S, Calabresi P, Cree B, Cross A, Davis M, Haines J, de Bakker P, Delgado S, Dembele M, Edwards K, Fitzgerald K, Hakonarson H, Konidari I, Lathi E, Manrique C, Pericak-Vance M, Piccio L, Schaefer C, McCabe C, Weiner H, Goldstein J, Olsson T, Hadjigeorgiou G, Taylor B, Tajouri L, Charlesworth J, Booth D, Harbo H, Ivinson A, Hauser S, Compston A, Stewart G, Zipp F, Barcellos L, Baranzini S, Martinelli-Boneschi F, D’Alfonso S, Ziegler A, Oturai A, McCauley J, Sawcer S, Oksenberg J, De Jager P, Kockum I, Hafler D, Cotsapas C. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell 2018, 175: 1679-1687.e7. PMID: 30343897, PMCID: PMC6269166, DOI: 10.1016/j.cell.2018.09.049.Peer-Reviewed Original ResearchMeSH KeywordsEpistasis, GeneticFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansLinkage DisequilibriumMaleMultiple SclerosisMutationOpen Reading FramesRisk FactorsConceptsRare coding variationsGenome-wide association studiesNon-coding variationCommon variant signalsSubstantial linkage disequilibriumLow-frequency variantsNovel genesCell homeostasisAssociation studiesComplex neurological diseasesLinkage disequilibriumGenetic variantsCommon variantsHeritabilityRich resourceGenesVariantsKey pathogenic roleIndividual familiesEpistasisAdditive effectBiologyHomeostasisMutationsNeurological diseases
2016
Multiple sclerosis
Axisa PP, Hafler DA. Multiple sclerosis. Current Opinion In Neurology 2016, 29: 345-353. PMID: 27058221, PMCID: PMC7882195, DOI: 10.1097/wco.0000000000000319.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkersDisease ProgressionGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansImmunologic FactorsMultiple SclerosisConceptsMultiple sclerosisGenome-wide association studiesAssociation studiesMultiple sclerosis (MS) etiologyMultiple sclerosis progressionMultiple sclerosis patientsHigh-throughput genetic analysisImmune cell functionNumerous candidate biomarkersWide association studyMechanisms of neurodegenerationImmunomodulatory treatmentSclerosis patientsClinical outcomesTreatment arsenalDisease progressionImmune regulationSclerosisNew biomarkersCandidate biomarkersPatient careGenetic variationGenetic analysisCell functionProgression
2015
Genetic basis of autoimmunity
Marson A, Housley WJ, Hafler DA. Genetic basis of autoimmunity. Journal Of Clinical Investigation 2015, 125: 2234-2241. PMID: 26030227, PMCID: PMC4497748, DOI: 10.1172/jci78086.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoimmune DiseasesAutoimmunityDatabases, GeneticGene Expression RegulationGene-Environment InteractionGenome-Wide Association StudyHumansConceptsGenetic basisInterpretation of GWASMultiple genomic datasetsWide association studyCommon human autoimmune diseasesRelevant cell typesCellular conditionsCellular phenotypesGenomic datasetsGene expressionDense genotypingBiological pathwaysAssociation studiesHuman autoimmune diseasesNucleotide variantsCell typesAutoimmune diseasesPrimary immune cellsUnbiased viewMonogenic mutationsPolygenic risk factorsEssential mechanismComplex disorderEnvironmental factorsNovel diagnosticsIntegrative analysis of 111 reference human epigenomes
Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller M, Amin V, Whitaker J, Schultz M, Ward L, Sarkar A, Quon G, Sandstrom R, Eaton M, Wu Y, Pfenning A, Wang X, ClaussnitzerYaping Liu M, Coarfa C, Alan Harris R, Shoresh N, Epstein C, Gjoneska E, Leung D, Xie W, David Hawkins R, Lister R, Hong C, Gascard P, Mungall A, Moore R, Chuah E, Tam A, Canfield T, Scott Hansen R, Kaul R, Sabo P, Bansal M, Carles A, Dixon J, Farh K, Feizi S, Karlic R, Kim A, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer T, Neph S, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari R, Siebenthall K, Sinnott-Armstrong N, Stevens M, Thurman R, Wu J, Zhang B, Zhou X, Abdennur N, Adli M, Akerman M, Barrera L, Antosiewicz-Bourget J, Ballinger T, Barnes M, Bates D, Bell R, Bennett D, Bianco K, Bock C, Boyle P, Brinchmann J, Caballero-Campo P, Camahort R, Carrasco-Alfonso M, Charnecki T, Chen H, Chen Z, Cheng J, Cho S, Chu A, Chung W, Cowan C, Athena Deng Q, Deshpande V, Diegel M, Ding B, Durham T, Echipare L, Edsall L, Flowers D, Genbacev-Krtolica O, Gifford C, Gillespie S, Giste E, Glass I, Gnirke A, Gormley M, Gu H, Gu J, Hafler D, Hangauer M, Hariharan M, Hatan M, Haugen E, He Y, Heimfeld S, Herlofsen S, Hou Z, Humbert R, Issner R, Jackson A, Jia H, Jiang P, Johnson A, Kadlecek T, Kamoh B, Kapidzic M, Kent J, Kim A, Kleinewietfeld M, Klugman S, Krishnan J, Kuan S, Kutyavin T, Lee A, Lee K, Li J, Li N, Li Y, Ligon K, Lin S, Lin Y, Liu J, Liu Y, Luckey C, Ma Y, Maire C, Marson A, Mattick J, Mayo M, McMaster M, Metsky H, Mikkelsen T, Miller D, Miri M, Mukame E, Nagarajan R, Neri F, Nery J, Nguyen T, O’Geen H, Paithankar S, Papayannopoulou T, Pelizzola M, Plettner P, Propson N, Raghuraman S, Raney B, Raubitschek A, Reynolds A, Richards H, Riehle K, Rinaudo P, Robinson J, Rockweiler N, Rosen E, Rynes E, Schein J, Sears R, Sejnowski T, Shafer A, Shen L, Shoemaker R, Sigaroudinia M, Slukvin I, Stehling-Sun S, Stewart R, Subramanian S, Suknuntha K, Swanson S, Tian S, Tilden H, Tsai L, Urich M, Vaughn I, Vierstra J, Vong S, Wagner U, Wang H, Wang T, Wang Y, Weiss A, Whitton H, Wildberg A, Witt H, Won K, Xie M, Xing X, Xu I, Xuan Z, Ye Z, Yen C, Yu P, Zhang X, Zhang X, Zhao J, Zhou Y, Zhu J, Zhu Y, Ziegler S, Beaudet A, Boyer L, De Jager P, Farnham P, Fisher S, Haussler D, Jones S, Li W, Marra M, McManus M, Sunyaev S, Thomson J, Tlsty T, Tsai L, Wang W, Waterland R, Zhang M, Chadwick L, Bernstein B, Costello J, Ecker J, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos J, Wang T, Kellis M. Integrative analysis of 111 reference human epigenomes. Nature 2015, 518: 317-330. PMID: 25693563, PMCID: PMC4530010, DOI: 10.1038/nature14248.Peer-Reviewed Original ResearchConceptsHuman epigenomeHuman diseasesIntegrative analysisReference human genome sequenceDiverse human traitsRoadmap Epigenomics ConsortiumHuman genome sequenceHistone modification patternsRelevant cell typesEpigenomic informationEpigenomic marksDNA accessibilityRegulatory modulesGene regulationEpigenomic studiesGenome sequenceDNA methylationGenetic variationRegulatory elementsCellular differentiationMolecular basisModification patternsEpigenomeHuman traitsCell types
2014
Genetic and epigenetic fine mapping of causal autoimmune disease variants
Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, Beik S, Shoresh N, Whitton H, Ryan RJ, Shishkin AA, Hatan M, Carrasco-Alfonso MJ, Mayer D, Luckey CJ, Patsopoulos NA, De Jager PL, Kuchroo VK, Epstein CB, Daly MJ, Hafler DA, Bernstein BE. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 2014, 518: 337-343. PMID: 25363779, PMCID: PMC4336207, DOI: 10.1038/nature13835.Peer-Reviewed Original ResearchConceptsCausal variantsAutoimmune diseasesT cellsRegulatory T cellsNon-coding risk variantsT cell subsetsEnhancer-associated RNAsGenome-wide association studiesPrimary immune cellsCandidate causal variantsGene regulatory modelsImmune cellsImmune stimulationB cellsGene activationFine mappingTranscription factorsMaster regulatorHistone acetylationImmune differentiationSequence determinantsGene expressionAssociation studiesDiseaseHuman diseasesPolarization 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 variantsCommon Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells
Lee MN, Ye C, Villani AC, Raj T, Li W, Eisenhaure TM, Imboywa SH, Chipendo PI, Ran FA, Slowikowski K, Ward LD, Raddassi K, McCabe C, Lee MH, Frohlich IY, Hafler DA, Kellis M, Raychaudhuri S, Zhang F, Stranger BE, Benoist CO, De Jager PL, Regev A, Hacohen N. Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells. Science 2014, 343: 1246980. PMID: 24604203, PMCID: PMC4124741, DOI: 10.1126/science.1246980.Peer-Reviewed Original ResearchMeSH KeywordsAdultAutoimmune DiseasesCommunicable DiseasesDendritic CellsEscherichia coliFemaleGene-Environment InteractionGenetic LociGenome-Wide Association StudyHEK293 CellsHost-Pathogen InteractionsHumansInfluenza A virusInterferon Regulatory Factor-7Interferon-betaLipopolysaccharidesMaleMiddle AgedPolymorphism, Single NucleotideQuantitative Trait LociSTAT Transcription FactorsTranscriptomeYoung AdultConceptsGenetic variationPathogen-responsive genesHuman genetic variationGenetic variantsIRF transcription factorsCommon genetic variantsType I IFN inductionFunctional annotationExpression responsesTranscription factorsI IFN inductionCausal variantsPathogen sensingEnvironmental stimuliComplex diseasesCommon variantsCommon allelesIFN inductionComputational approachVariantsCellsInductionGenesInterindividual variationSTAT
2013
Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
Patsopoulos NA, Barcellos LF, Hintzen RQ, Schaefer C, van Duijn CM, Noble JA, Raj T, , , Gourraud PA, Stranger BE, Oksenberg J, Olsson T, Taylor BV, Sawcer S, Hafler DA, Carrington M, De Jager PL, de Bakker PI. Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects. PLOS Genetics 2013, 9: e1003926. PMID: 24278027, PMCID: PMC3836799, DOI: 10.1371/journal.pgen.1003926.Peer-Reviewed Original ResearchMeSH KeywordsAllelesChromosome MappingGenetic Predisposition to DiseaseGenome-Wide Association StudyHaplotypesHistocompatibility Antigens Class IHLA-DP beta-ChainsHLA-DRB1 ChainsHumansIntracellular Signaling Peptides and ProteinsLinkage DisequilibriumMajor Histocompatibility ComplexMembrane ProteinsMultiple SclerosisPolymorphism, Single NucleotideReceptors, Tumor Necrosis Factor, Type IConceptsHuman leukocyte antigenNon-HLA risk allelesRisk allelesClassical human leukocyte antigenClass IMultiple sclerosis susceptibilityHLA class IIndependent effectsMS susceptibility geneMajor histocompatibility complexMajor histocompatibility complex regionHLA effectMultiple sclerosisLeukocyte antigenHLA-DRB1MS susceptibilityMultiple risk allelesDPB1 allelesClass IIPeptide-binding grooveHistocompatibility complexPolymorphic amino acid positionsTNF geneClassical allelesSusceptibility genesNetwork-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
2012
Immune-mediated disease genetics: the shared basis of pathogenesis
Cotsapas C, Hafler DA. Immune-mediated disease genetics: the shared basis of pathogenesis. Trends In Immunology 2012, 34: 22-26. PMID: 23031829, DOI: 10.1016/j.it.2012.09.001.Peer-Reviewed Original ResearchMeSH KeywordsGenetic Predisposition to DiseaseGenetic TestingGenome-Wide Association StudyHumansImmune SystemRisk FactorsConceptsRecent genetic studiesGenomic lociDisease geneticsMolecular basisGenetic studiesMolecular causesMolecular defectsRisk variantsSpecific pathwaysBasis of pathogenesisActionable discoveriesGeneticsInflammatory diseasesOverall symptomatologyDisease heterogeneityLociVariantsDiseasePathwayPathogenesisHigh rateRational approachDiscoveryPathobiologyMultiple sclerosis
Nylander A, Hafler DA. Multiple sclerosis. Journal Of Clinical Investigation 2012, 122: 1180-1188. PMID: 22466660, PMCID: PMC3314452, DOI: 10.1172/jci58649.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAutoantigensAutoimmune DiseasesB-Lymphocyte SubsetsCostimulatory and Inhibitory T-Cell ReceptorsCytokinesForecastingForkhead Transcription FactorsGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansLymphocyte ActivationMeningesModels, ImmunologicalMultiple SclerosisT-Lymphocyte SubsetsT-Lymphocytes, RegulatoryConceptsMultiple sclerosisImmunopathology of MSMultifocal demyelinating diseasePersistence of antigenMS prognosisDemyelinating diseaseOligoclonal expansionAutoimmune responseLymphoid folliclesHumoral responseT cellsTreatment decisionsInfectious agentsSusceptible individualsProgressive neurodegenerationCommon genetic variantsPathway disruptionPresent recent dataSclerosisRecent dataDisease susceptibilityAntigenGenetic variantsImmunopathologyPrognosisUnraveling the autoimmune translational research process layer by layer
Blumberg RS, Dittel B, Hafler D, von Herrath M, Nestle FO. Unraveling the autoimmune translational research process layer by layer. Nature Medicine 2012, 18: 35-41. PMID: 22227670, PMCID: PMC4592149, DOI: 10.1038/nm.2632.Peer-Reviewed Original ResearchMeSH KeywordsAutoimmune DiseasesDrug ApprovalGenome-Wide Association StudyHumansTranslational Research, BiomedicalUnited StatesUnited States Food and Drug Administration
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 consequencesGenome-Wide Assessment for Genetic Variants Associated with Ventricular Dysfunction after Primary Coronary Artery Bypass Graft Surgery
Fox AA, Pretorius M, Liu KY, Collard CD, Perry TE, Shernan SK, De Jager PL, Hafler DA, Herman DS, DePalma SR, Roden DM, Muehlschlegel JD, Donahue BS, Darbar D, Seidman JG, Body SC, Seidman CE. Genome-Wide Assessment for Genetic Variants Associated with Ventricular Dysfunction after Primary Coronary Artery Bypass Graft Surgery. PLOS ONE 2011, 6: e24593. PMID: 21980348, PMCID: PMC3184087, DOI: 10.1371/journal.pone.0024593.Peer-Reviewed Original ResearchConceptsCABG surgeryPostoperative ventricular dysfunctionVentricular dysfunctionSingle nucleotide polymorphismsPrimary coronary artery bypass graft surgeryCoronary artery bypass graft surgeryArtery bypass graft surgeryPrimary CABG surgeryBypass graft surgeryClinical risk factorsMechanical ventricular supportPatient risk stratificationGenetic variantsCABG cohortGraft surgeryPostoperative morbiditySurgical patientsCardiopulmonary bypassRisk stratificationVentricular supportRisk factorsLarge cohortPrevention strategiesSurgeryMale subjectsPervasive Sharing of Genetic Effects in Autoimmune Disease
Cotsapas C, Voight BF, Rossin E, Lage K, Neale BM, Wallace C, Abecasis GR, Barrett JC, Behrens T, Cho J, De Jager PL, Elder JT, Graham RR, Gregersen P, Klareskog L, Siminovitch KA, van Heel DA, Wijmenga C, Worthington J, Todd JA, Hafler DA, Rich SS, Daly MJ, . Pervasive Sharing of Genetic Effects in Autoimmune Disease. PLOS Genetics 2011, 7: e1002254. PMID: 21852963, PMCID: PMC3154137, DOI: 10.1371/journal.pgen.1002254.Peer-Reviewed Original ResearchMeSH KeywordsAutoimmune DiseasesCluster AnalysisComorbidityGenetic LociGenome-Wide Association StudyHumansPhenotypePolymorphism, Single NucleotideProtein Interaction MapsConceptsSingle nucleotide polymorphismsSystemic lupus erythematosusImmune-mediated diseasesType 1 diabetesGenetic risk factorsMajor histocompatibility locusCommon autoimmuneCommon single nucleotide polymorphismsLupus erythematosusCrohn's diseaseRheumatoid arthritisClinical evidenceMultiple sclerosisAutoimmune diseasesRisk single nucleotide polymorphismsCeliac diseaseInflammatory diseasesRisk factorsMeta-AnalysisDisease riskDiseaseHistocompatibility locusUnderlying mechanismGenetic associationNucleotide polymorphisms