Evidence for X-Chromosomal Schizophrenia Associated with microRNA Alterations 英文参考文献.docVIP

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Evidence for X-Chromosomal Schizophrenia Associated with microRNA Alterations 英文参考文献.doc

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Evidence for X-Chromosomal Schizophrenia Associated with microRNA Alterations 英文参考文献

EvidenceforX-ChromosomalSchizophreniaAssociated withmicroRNAAlterations JinongFeng1,GuihuaSun2,3,JinYan1,KatieNoltner1,WenyanLi1,CarolynH.Buzin1,6,JeffLongmate4, LeonardL.Heston5,JohnRossi2,SteveS.Sommer1,6* 1DivisionofMolecularGenetics,CityofHopeNationalMedicalCenter,Duarte, California,UnitedStatesofAmerica, 2Department ofMolecularBiology,CityofHope National Medical Center, Duarte, California, United States of America, 3Graduate School, City of Hope National Medical Center, Duarte, California, United States of America,4DivisionofInformationSciences,CityofHopeNationalMedicalCenter,Duarte,California,UnitedStatesofAmerica,5DepartmentofPsychiatry,Universityof Washington,Seattle,Washington,UnitedStatesofAmerica,6MEDomics,Azusa,California,UnitedStatesofAmerica Abstract Background:Schizophreniaisaseveredisablingbraindiseaseaffectingabout1%ofthepopulation.IndividualmicroRNAs (miRNAs)affectmoderatedownregulationofgeneexpression.Inaddition,componentsrequiredformiRNAprocessingand/ orfunctionhavealsobeenimplicatedinX-linkedmentalretardation,neurologicalandneoplasticdiseases,pointingtothe wideranginginvolvementofmiRNAsindisease. MethodsandFindings:ToexploretheroleofmiRNAsinschizophrenia,59microRNAgenesontheX-chromosomewere amplifiedandsequencedinmaleswith(193)andwithout(191)schizophreniaspectrumdisorderstotestthehypothesis that ultra-rare mutations in microRNA collectively contribute to the risk of schizophrenia. Here we provide the first associationofmicroRNAgenedysfunctionwithschizophrenia.Eightultra-rarevariantsintheprecursorormaturemiRNA were identified in eight distinct miRNA genes in 4% of analyzed males with schizophrenia. One ultra-rare variant was identifiedinacontrolsample(withahistoryofdepression)(8/193versus1/191,p=0.02byone-sidedFisher’sexacttest, oddsratio=8.2).Thesevariantswerenotfoundinanadditional7,197controlX-chromosomes. Conclusions: Functional analyses of ectopically expressed copies of the variant miRNA precursors demonstrate loss of function,gain