Common-variants-on-8p12-and-1q24.2-confer-risk-of-

©2011NatureAmerica,Inc.Allrightsreserved.©2011NatureAmerica,Inc.Allrightsreserved.1224 VOLUME43|NUMBER12|DECEMBER2011NatureGeNeticsSchizophrenia is a severe mental disorder affecting ~1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10−10) and 1q24.2 (rs10489202, P = 9.50 × 10−9). Our findings provide new insights into the pathogenesis of schizophrenia.Schizophreniaisasevereneuropsychiatricdisordercharacterizedbypsychoticbehavior(delusionandhallucinations),disorganiza-tion,dysfunctioninnormalaffectiveresponsesandalteredcognitivefunctioning1.Recentgenome-widestudiesofpopulationsofEuropeanancestryhaverevealedbothcommon,low-riskSNPsandrare,high-penetrancecopy-numbervariantspredisposingindividualstoschizophrenia2–8.However,muchoftheheritabilityofschizophreniaremainsunaccountedfor,andthepathwaysorbiologicalmechanismsthatunderliesusceptibilityarestilllargelyunknown.Tosearchforcommonvariantsassociatedwithschizophrenia,weperformedaGWASof3,750individualswithschizophreniaand6,468healthycontrolsgenotypedusingAffymetrixSNP6.0GeneChipsinHanChinesepopulationsfromthreegeographiclocations(northern,centralandsouthernChina).Intotal,546,561SNPswereusedforstatisticalanalysisafterqualitycontrolfilteringintheinitialstudies.LogisticregressionwasusedtotesttheadditiveeffectsofminoralleledosageforeachSNP.Potentialpopulationstratificationwasadjustedforusingeigenvectorsfromprincipal-componentanalysis(PCA)(seeOnlineMethods).Wecarriedoutagenome-widecombinedanalysisinthreeinde-pendentcohortsinthediscoverystageandthenfurtheranalyzedthemostsignificantlyassociatedSNPsinadditionalsamples.Initially,weperformedaGWASthatincluded(i)1,578subjectswithschizophreniaCommonvariantson8p12and1q24.2conferriskofschizophreniaYongyongShi1–3,32,ZhiqiangLi1,2,32,QiXu4,32,TiWang1,TaoLi1,JiaweiShen1,FengyuZhang5,JianhuaChen6,GuoquanZhou3,WeidongJi3,BaojieLi1,YifengXu6,DengtangLiu6,PengWang7,PingYang7,BenxiuLiu8,WenshengSun8,ChunlingWan1,ShengyingQin1,2,GuangHe1,2,StacySteinberg9,SvenCichon10–12,ThomasWerge13,EngilbertSigurdsson14,SarahTosato15,AarnoPalotie16–20,MarkusMNöthen10,11,21,MarcellaRietschel22,23,RoelAOphoff24–26,DavidACollier27,DanRujescu28,DavidStClair29,HreinnStefansson9,KariStefansson9,JueJi1,QingzhongWang1,WenjinLi1,LinqingZheng1,HairongZhang1,GuoyinFeng5&LinHe1,2,30,311Bio-XInstitutes,KeyLaboratoryfortheGeneticsofDevelopmentalandNeuropsychiatricDisorders,MinistryofEducation,ShanghaiJiaoTongUniversity,Shanghai,China.2ShanghaigenomePilotInstitutesforGenomicsandHumanHealth,Shanghai,China.3ChangningMentalHealthCenter,Shanghai,China.4NationalLaboratoryofMedicalMolecularBiology,InstituteofBasicMedicalSciences,ChineseAcademyofMedicalSciences&PekingUnionMedicalCollege,Beijing,China.5Genes,CognitionandPsychosisProgram,NationalInstituteofMentalHealth,theNationalInstitutesofHealth,Bethesda,Maryland,USA.6ShanghaiInstituteofMentalHealth,Shanghai,China.7FourthPeople’sHospital,Wuhu,China.8LongquanMountainHospitalofGuangxiProvince,Liuzhou,China.9deCODEgenetics,Reykjavik,Iceland.10DepartmentofGenomics,LifeandBrainCenter,UniversityofBonn,Bonn,Germany.11InstituteofHumanGenetics,UniversityofBonn,Bonn,Germany.12InstituteofNeuroscienceandMedicine(INM-1),StructuralandFunctionalOrganizationoftheBrainGenomicImaging,ResearchCenterJuelich,Juelich,Germany.13InstituteofBiologicalPsychiatry,MentalHealthCentreSaintHans,CopenhagenUniversityHospital,Roskilde,Denmark.14DepartmentofPsychiatry,NationalUniversityHospital,Reykjavik,Iceland.15SectionofPsychiatryandClinicalPsychology,UniversityofVerona,Verona,Italy.16WellcomeTrustSangerInstitute,WellcomeTrustGenomeCampus,Hinxton,Cambridge,UK.17InstituteforMolecularMedicineFinland(FIMM),UniversityofHelsinki,Helsinki,Finland.18PrograminMedicalandPopulationGeneticsandGeneticAnalysisPlatform,TheBroadInstituteofMITandHarvard,Cambridge,Massachusetts,USA.19DepartmentofMedicalGenetics,UniversityofHelsinki,Helsinki,Finland.20DepartmentofMedicalGenetics,HelsinkiUniversityCentralHospital,Helsinki,Finland.21GermanCenterforNeurodegenerativeDisorders,Bonn,Germany.22DepartmentofGeneticEpidemiologyinPsychiatry,CentralInstituteofMentalHealth,UniversityofHeidelberg,Mannheim,Germany.23DepartmentofPsychiatry,UniversityofBonn,Bonn,Germany.24RudolfMagnusInstituteofNeuroscience,UniversityMedicalCenterUtrecht,Utrecht,TheNetherlands.25DepartmentofMedicalGenetic