biostudies-literatureRuzicka WBNIDA NIH HHSNIA NIH HHSNIMH NIH HHSeadg5136https://www.ebi.ac.uk/biostudies/studies/S-EPMC12772489biostudies-literatureUnknown384(6698)The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence of rare and common genomic variants on neuronal population-specific alterations in schizophrenia. Based on the magnitude of schizophrenia-associated transcriptional change, we identified two populations of individuals with schizophrenia marked byScience (New York, N.Y.)Single-cell multi-cohort dissection of the schizophrenia transcriptome.PMC12772489R21 MH105881U01 MH122678R01 MH117406R01 MH116438U01 MH122592U01 MH122590U01 MH122591R21 MH129817R01 MH117291R01 MH105898R01 MH117293R01 MH109978R01 MH117292R01 MH126393R01 MH116529R21 MH103877R21 MH105853R01 MH110905HHSN271201300031CU01 MH119509U01 MH122509R01 MH125516U01 MH116492U01 MH103339R21 MH102791R01 AG050986K08 MH109759R01 MH111721R01 AG067025R01 MH109715R01 AG062335R01 MH109677R01 MH121521U01 MH116489R01 MH105472R01 MH126459U01 MH116487U01 MH116488U01 MH116441R01 MH125246U01 MH116442R56 MH114901U01 MH103346R01 MH110920U01 MH122681R21 MH109956K08 MH122911U01 MH103340R01 MH110927R01 MH110928R01 MH094714U01 MH103392R01 MH110926P50 MH106934R01 MH110921U01 DA048279U01 MH122849Gaynor SLin XZiffra RKawaguchi RReimonn TAkbarian STherrien KRuth MWhite KPAlmagro Armenteros JJSudhof TDavila-Velderrain JHe CYap CXMargolis MRozowsky JNairn ACPeters MAInoue FZeng BWylie DDursun CPage SCQuintero DSchneider JMXu SAhituv NHenry EGerstein MChampagne FAMeng RWuchty SSebra RSestan NStein JNemeroff CBPollard KSWei YDrusinsky SQin ZSRessler KJSnijders CZintel TMPhalke NBicks LRoss DMyers RMWeimer AKJajoo AHourihan MChien JFHallmayer JBendl JKellis MWong WHuuki-Myers LADeng CHawken NPollen AMicallef CPjanic MMazariegos SSnyder MTsai LHClement ACrawford GEDiPietro CPChess AGoes FSMukamel EAArasappan DLou SPrzytycki PFGupta CVo DChen YChatterjee TKozlenkov ALi JDaskalakis NPCooper GMKundaje ALi MBharadwaj RASteyert MKleopoulos SPEdelstein JLee HCLiu JJiang LJourdon AMa SMa LSubburaju SJiang SShieh AWLiu SJensen MShin JHDeep-Soboslay AMing GLJops CPattni RMariani JVaccarino FMOmberg LSkarica MKleinman JEPatowary AShedd NFullard JFEmani PSZhang YHwang ALiu CZhang JMaynard KRChen HIGuo QHyde TMZhang PGalani KGuo HScuderi SMoore JEPertea GEagles NJHoffman GEJin PZhang CZhang BPochareddy STso DRZeier ZRHadas YJin TChu ZHicks SCRuzicka WBHo LLHaroutunian VGirdhar KNorton Svan Bakel HWarrell JHan XCheng YLee DMohammadi SLee CShao ZGreenleaf WCheng LNowakowski TReach SMontgomery KSCollado-Torres LDuong DCapauto DBeliveau BJZhou XNi PChatzinakos CWang SHHuang YDai RClarke DMikhailova TKriegstein ADracheva SBrennand KGrundman JWang DMoran JRWu FWu HPsychENCODE Consortium§Voloudakis GWang TWeng ZWen CWang YBerretta SRoussos PGaleev TLu DMonte EPark SPsychENCODE ConsortiumPratt HHo MPinto DSanders SJRajagopalan ASWamsley BWhalen SMartinowich KState MWUrban AEAbyzov AGeschwind DHRaj TWillsey AJWon HIatrou AGandal MJSong HDuan ZLoupe JMBhattacharya AQu PPPurmann CTao RWeinberger DRSeyfried NKundu SfalseSingle-cell multi-cohort dissection of the schizophrenia transcriptome.The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence of rare and common genomic variants on neuronal population-specific alterations in schizophrenia. Based on the magnitude of schizophrenia-associated transcriptional change, we identified two populations of individuals with schizophrenia marked by2024-01-01T00:00:00Z2024 May2026-06-06T10:54:36.289Z2026-05-29T03:12:25.898ZS-EPMC127724893878138810.1126/science.adg5136