/Users/andrea/_magisterarbeit/korpus/clean/trainkorpus/1/file4.html NN ----------------------------------------- : Skip NP to TO content VV . SENT HomeCurrent NP IssueNew NP ArticlesArchiveSubmit NP PaperContent NP Alerts VVZ PLoSPLoS NP Biology NN Order NP Print NP Issues NPS Contact NP Us NP Author NN Info NP Reviewer NN Info NP Journal NP Info NP Ed NP Board NP Help NN Volume NN 2 CD Issue NN 7 CD JULY NP 2005 CD Previous JJ article NN Next JJ article NN SEARCH NN PLoS NP Medicine NP Advanced NP Search NP Research NP in IN Translation NN The DT Genetics NP of IN SchizophreniaPatrick NP F NP . SENT SullivanPatrick NP F NP . SENT Sullivan NP is VBZ at IN the DT Departments NP of IN Genetics NP , , Psychiatry NP , , and CC Epidemiology NN at IN the DT University NP of IN North NP Carolina NP at IN Chapel NP Hill NP , , United NP States NPS . SENT E SYM mail NN . SENT pfsulliv NP med NP . SENT unc NN . SENT edu NN Competing VVG Interests NNS . SENT The DT author NN declares VVZ that IN he PP has VHZ no DT competing VVG interests NNS . SENT Published VVN . SENT July NP 26 CD , , 2005 CD DOI NP . SENT 10 CD . SENT 1371 CD journal NN . SENT pmed JJ . SENT 0020212 CD Copyright NN . SENT 2005 CD Patrick NP F NN . SENT Sullivan NP . SENT This DT is VBZ an DT open JJ access NN article NN distributed VVN under IN the DT terms NNS of IN the DT Creative JJ Commons NP Attribution NN License NN , , which WDT permits VVZ unrestricted JJ use NN , , distribution NN , , and CC reproduction NN in IN any DT medium NN , , provided VVD the DT original JJ work NN is VBZ properly RB cited VVN . SENT Citation NP . SENT Sullivan NP PF NP 2005 CD The NP Genetics NP of IN Schizophrenia NN . SENT PLoS NP Med NP 2 CD 7 CD . SENT e SYM 212 CD Research NN into IN the DT etiology NN of IN schizophrenia NN has VHZ never RB been VBN as RB interesting JJ or CC as RB provocative JJ as IN in IN the DT past JJ three CD years NNS . SENT There EX has VHZ been VBN progress NN on IN several JJ fronts NNS , , but CC particularly RB regarding VVG the DT molecular JJ genetics NN of IN this DT complex JJ disorder NN of IN mind NN and CC brain NN . SENT At IN the DT same JJ time NN , , a DT number NN of IN critically RB important JJ and CC unresolved JJ issues NNS remain VVP that RB qualify VV the DT ultimate JJ clinical JJ and CC scientific JJ validity NN of IN the DT results NNS . SENT However RB , , the DT recent JJ progress NN in IN this DT historically RB difficult JJ area NN of IN inquiry NN does VVZ not RB seem VV to TO be VB widely RB appreciated VVN . SENT The DT purpose NN of IN this DT article NN is VBZ to TO provide VV a DT high JJ level NN review NN of IN progress NN , , its PP$ limitations NNS , , and CC the DT implications NNS for IN clinical JJ research NN and CC clinical JJ practice NN . SENT The DT public JJ health NN importance NN of IN schizophrenia NN is VBZ clear JJ . SENT The DT median JJ lifetime NN prevalence NN of IN schizophrenia NN is VBZ 0 CD . SENT 7 CD 0 CD . SENT 8 CD 1 CD , , with IN onset NN typically RB ranging VVG from IN adolescence NN to TO early JJ adulthood NN and CC a DT course NN of IN illness NN typified VVD by IN exacerbations NNS , , remissions NNS , , and CC substantial JJ residual JJ symptoms NNS and CC functional JJ impairment NN 2 CD . SENT Morbidity NN is VBZ substantial JJ , , and CC schizophrenia NN ranks NNS ninth JJ in IN global JJ burden NN of IN illness NN 3 CD . SENT In IN addition NN , , schizophrenia NN is VBZ often RB comorbid JJ with IN drug NN dependence NN principally RB alcohol NN , , nicotine NN , , cannabis NN , , and CC cocaine NN and CC important JJ medical JJ conditions NNS obesity NN , , Type NN 2 CD diabetes NN mellitus NN 4 CD . SENT Mortality NN due JJ to TO natural JJ and CC unnatural JJ causes NNS is VBZ considerable JJ , , and CC the DT projected VVN lifespan NN for IN individuals NNS with IN schizophrenia NN is VBZ some DT 15 CD years NNS less RBR than IN the DT general JJ population NN 5 CD . SENT The DT personal JJ , , familial JJ , , and CC societal JJ costs NNS of IN schizophrenia NN are VBP enormous JJ . SENT Etiological JJ Clues NNS A DT substantial JJ body NN of IN epidemiological JJ research NN has VHZ established VVN a DT set NN of IN risk NN factors NNS for IN schizophrenia NN . SENT A DT subset NN of IN this DT work NN is VBZ summarized VVD in IN Figure NP 1 CD . SENT Of IN a DT large JJ set NN of IN pre NP and CC antenatal JJ risk NN factors NNS 6 CD , , having VHG a DT first JJ degree NN relative NN with IN schizophrenia NN is VBZ associated VVN with IN an DT odds NNS ratio NN of IN almost RB ten CD . SENT The DT general JJ impact NN of IN some DT of IN the DT risk NN factors NNS in IN Figure NN 1 CD remains VVZ uncertain JJ , , and CC , , additionally RB , , migrant JJ status NN , , urban JJ residence NN , , cannabis NN use NN , , and CC biological JJ sex NN are VBP supported VVN as IN risk NN factors NNS for IN schizophrenia NN . SENT Although IN the DT attributable JJ risk NN of IN some DT of IN these DT risk NN factors NNS may MD be VB greater JJR e NN . SENT g NN . SENT , , place NN and CC season NN of IN birth NN 7 CD , , the DT size NN of IN the DT odds NNS ratio NN for IN family NN history NN suggests VVZ that IN searching VVG for IN the DT familial JJ determinants NNS of IN schizophrenia NN is VBZ rational JJ for IN etiological JJ research NN . SENT Figure NN 1 CD . SENT Comparison NN of IN a DT Selected JJ Set NN of IN Relatively RB Well RB Established VVN Risk NN Factors NNS for IN Schizophrenia NN , , Focusing VVG Mainly RB on IN Pre NP and CC Antenatal JJ Factors NNS 6 CD abbreviations NNS . SENT CNS NP , , central JJ nervous JJ system NN . SENT depr NP , , depression NN . SENT Rh NP , , Rhesus NN Unpacking VVG the DT Family NP History NN Risk NP Factor NP Studies NPS of IN families NNS , , adoptees NNS , , and CC twins NNS have VHP been VBN widely RB used VVN to TO attempt VV to TO understand VV the DT relative JJ contributions NNS of IN genetic JJ and CC environmental JJ effects NNS upon IN risk NN for IN schizophrenia NN . SENT These DT old JJ genetics NN approaches NNS use VVP phenotypic JJ resemblance NN of IN relatives NNS as IN an DT indirect JJ means NN by IN which WDT to TO infer VV the DT roles NNS of IN genes NNS and CC environment NN . SENT There EX are VBP many JJ important JJ assumptions NNS and CC methodological JJ issues NNS with IN these DT studies NNS 8 CD . SENT however RB , , genetic JJ epidemiological JJ studies NNS of IN schizophrenia NN have VHP yielded VVN a DT remarkably RB consistent JJ set NN of IN findings NNS , , as RB summarized VVD in IN Table NN 1 CD 9 CD , , 10 CD . SENT Table NN 1 CD . SENT Summary NN of IN Studies NNS of IN the DT Genetic JJ Epidemiology NN of IN SchizophreniaTo NP summarize VV this DT literature NN briefly NN , , schizophrenia NN is VBZ familial JJ , , or CC runs VVZ in IN families NNS . SENT Both DT adoption NN and CC twin JJ studies NNS indicate VVP that IN the DT familiality NN of IN schizophrenia NN is VBZ due JJ mainly RB to TO genetic JJ effects NNS . SENT Twin JJ studies NNS suggest VVP the DT relevance NN of IN small JJ but CC significant JJ shared JJ environmental JJ influences NNS that WDT are VBP likely RB prenatal JJ in IN origin NN . SENT Thus RB , , schizophrenia NN is VBZ best RBS viewed VVN as IN a DT complex JJ trait NN resulting VVG from IN both DT genetic JJ and CC environmental JJ etiological JJ influences NNS . SENT These DT results NNS are VBP only RB broadly RB informative JJ , , as IN they PP provide VVP no DT information NN about IN the DT location NN of IN the DT genes NNS or CC the DT identity NN of IN the DT environmental JJ factors NNS that WDT predispose VV or CC protect VV against IN schizophrenia NN . SENT Searching VVG for IN genetic JJ influences NNS that WDT mediate VV vulnerability NN to TO schizophrenia NN is VBZ rational JJ , , given VVN the DT larger JJR overall JJ effect NN size NN and CC lesser JJR error NN of IN measurement NN in IN comparison NN to TO typical JJ assessments NNS of IN environmental JJ effects NNS . SENT Note NN that IN high JJ heritability NN is VBZ no DT guarantee NN of IN success NN in IN efforts NNS to TO identify VV candidate NN genes NNS . SENT Genomewide JJ Linkage NN Studies NNS of IN Schizophrenia NN Modern NP genotyping NN technologies NNS and CC statistical JJ analyses NNS have VHP enabled VVN the DT discovery NN of IN genetic JJ loci NNS related VVN to TO the DT etiology NN of IN many JJ complex JJ traits NNS 11 CD , , such JJ as IN Type NN 2 CD diabetes NN mellitus NN , , obesity NN , , and CC Alzheimer's NP disease NN . SENT These DT discovery NN science NN approaches NNS have VHP been VBN applied VVN to TO schizophrenia NN , , and CC are VBP summarized VVN in IN Figure NP 2 CD . SENT The DT 27 CD samples NNS shown VVN here RB included VVD from IN one CD to TO 294 CD multiplex NN pedigrees NNS see VVP Glossary NN median NN 34 CD containing VVG 32 CD to TO 669 CD median NN 101 CD individuals NNS affected VVN with IN a DT narrow JJ definition NN of IN schizophrenia NN . SENT There EX were VBD 310 CD to TO 950 CD median NN 392 CD genetic JJ markers NNS in IN the DT first JJ stage NN genome NN scans VVZ . SENT Figure NN 2 CD . SENT Summary NN of IN Genomewide NP Linkage NN Studies NNS of IN SchizophreniaThe NP x SYM axis NN shows VVZ the DT location NN on IN the DT genome NN , , from IN the DT telomere NN of IN the DT short JJ arm NN of IN Chromosome NN 1 CD to TO the DT telomere NN of IN the DT long JJ arm NN of IN Chromosome NN 22 CD bottom NN row NN along IN with IN 303 CD band NN chromosomal JJ staining VVG on IN the DT second JJ to TO bottom JJ row NN . SENT The DT y NP axis NN shows VVZ the DT 27 CD primary JJ samples NNS that WDT reported VVD first JJ stage NN genome NN scans VVZ for IN schizophrenia NN i NP . SENT e SYM . SENT , , excluding VVG fine JJ mapping NN or CC partial JJ reports NNS along IN with IN the DT results NNS of IN a DT meta NP analysis NN including VVG most JJS of IN the DT primary JJ samples NNS 12 CD studies NNS not RB included VVN are VBP shown VVN with IN asterisks NNS . SENT Within IN each DT row NN , , the DT height NN and CC color NN of IN the DT bars NNS are VBP proportional JJ to TO the DT log NN 10 CD P NN value NN , , and CC the DT width NN of IN the DT bar NN shows VVZ the DT genomic JJ location NN implicated VVN by IN a DT particular JJ sample NN . SENT A DT selected JJ set NN of IN candidate NN genes NNS for IN schizophrenia NN are VBP also RB shown VVN . SENT All DT genomic JJ locations NNS are VBP per IN the DT hg NN 16 CD build VVP http NN . SENT genome NN . SENT ucsc NN . SENT edu NN . SENT The DT physical JJ positions NNS of IN an DT inclusive JJ set NN of IN the DT markers NNS showing VVG the DT best JJS findings NNS in IN the DT primary JJ samples NNS were VBD plotted VVD assuming VVG a DT confidence NN interval NN of IN 10 CD cM NN or CC , , if IN mapping NN was VBD uncertain JJ , , 10 CD megabases NNS . SENT seven CD markers NNS from IN the DT primary JJ samples NNS did VVD not RB map VV . SENT Hard JJ replication NN implication NN of IN the DT same JJ markers NNS , , alleles NNS , , and CC haplotypes NNS in IN the DT majority NN of IN samples NNS is VBZ elusive JJ . SENT It PP is VBZ evident JJ from IN Figure NP 2 CD that IN these DT studies NNS are VBP inconsistent JJ , , and CC no DT genomic JJ region NN was VBD implicated VVN in IN more JJR than IN four CD of IN the DT 27 CD samples NNS . SENT The DT Lewis NP et NP al NP . SENT meta NP analysis NN 12 CD included VVD most JJS of IN the DT studies NNS in IN Figure NP 2 CD and CC found VVD that IN one CD region NN on IN Chromosome NN 2 CD was VBD stringently RB significant JJ and CC several JJ additional JJ regions NNS neared VVD significance NN . SENT Our PP$ focus NN on IN first JJ stage NN genome NN scans NNS does VVZ not RB adequately RB capture VV the DT evidence NN supporting VVG replication NN for IN certain JJ regions NNS e NN . SENT g NN . SENT , , 6 CD p NN 13 CD 18 CD . SENT However RB , , there EX appears VVZ to TO be VB soft JJ replication NN across IN studies NNS . SENT It PP is VBZ unlikely JJ that IN all DT of IN these DT linkage NN findings NNS are VBP true JJ . SENT The DT regions NNS suggested VVD by IN the DT Lewis NP et NP al NP . SENT meta NP analysis NN implicate VV more JJR than IN 3 CD , , 000 CD genes NNS 18 CD of IN all DT known VVN genes NNS . SENT For IN the DT 27 CD samples NNS in IN Figure NP 2 CD , , the DT percentages NNS of IN all DT known VVN genes NNS implicated VVN by IN 0 CD , , 1 CD , , 2 CD , , 3 CD , , and CC 4 CD linkage NN studies NNS were VBD 42 CD , , 35 CD , , 14 CD , , 6 CD , , and CC 3 CD , , respectively RB . SENT This DT crude JJ summation NN suggests VVZ that DT linkage NN analysis NN is VBZ an DT imprecise JJ tool NN implausibly RB large JJ numbers NNS of IN genes NNS are VBP implicated VVN and CC few JJ genes NNS are VBP consistently RB identified VVN in IN more JJR than IN a DT small JJ subset NN of IN studies NNS . SENT There EX are VBP several JJ potential JJ reasons NNS why WRB clear JJ cut NN or CC hard JJ replication NN was VBD not RB found VVN . SENT With IN respect NN to TO the DT teams NNS that WDT conducted VVD these DT enormously RB effortful JJ studies NNS , , it PP is VBZ possible JJ that IN no DT study NN possessed VVD sufficient JJ statistical JJ power NN to TO detect VV the DT subtle JJ genetic JJ effects NNS suspected VVN for IN schizophrenia NN . SENT For IN example NN , , it PP would MD require VV 4 CD , , 900 CD pedigrees NNS to TO have VH 80 CD power NN to TO detect VV a DT locus NN accounting NN for IN 5 CD of IN variance NN in IN liability NN to TO schizophrenia NN at IN 0 CD . SENT 001 CD . SENT These DT calculations NNS make VVP highly RB optimistic JJ assumptions NNS , , and CC less JJR favorable JJ assumptions NNS can MD lead VV to TO sample NN size NN requirements NNS above IN 50 CD , , 000 CD sibling NN pairs NNS . SENT For IN comparison NN , , the DT total JJ number NN of IN pedigrees NNS in IN Figure NP 2 CD is VBZ less JJR than IN 2 CD , , 000 CD . SENT In IN addition NN , , it PP is VBZ possible JJ that IN etiological JJ heterogeneity NN different JJ combinations NNS of IN genetic JJ and CC environmental JJ causes NNS between IN samples NNS and CC technical JJ differences NNS different JJ ascertainment NN , , assessment NN , , genotyping NN , , and CC statistical JJ analysis NN between IN samples NNS contributed VVD . SENT however RB , , their PP$ impact NN is VBZ uncertain JJ , , whereas IN insufficient JJ power NN is VBZ clear JJ . SENT If IN correct JJ , , the DT implication NN is VBZ that IN Figure NN 2 CD contains VVZ a DT mix NN of IN true JJ and CC false JJ positive JJ findings NNS . SENT Association NP Studies NPS of IN Schizophrenia NN Schizophrenia NN like IN most RBS other JJ complex JJ traits NNS in IN biomedicine NN has VHZ had VHN a DT large JJ number NN of IN genetic JJ case NN control NN association NN studies NNS 19 CD . SENT Although IN research NN practice NN is VBZ changing VVG , , interpretation NN of IN many JJ studies NNS is VBZ hindered VVN by IN small JJ sample NN sizes NNS and CC a DT tendency NN to TO genotype NN a DT single JJ genetic JJ marker NN of IN the DT hundreds NNS that WDT might MD be VB available JJ in IN a DT gene NN . SENT For IN example NN , , a DT widely RB studied VVN functional JJ genetic JJ marker NN in IN COMT NP rs NP 4680 CD is VBZ probably RB not RB associated VVN with IN schizophrenia NN 20 CD , , but CC nearby JJ genetic JJ markers NNS assessed VVN in IN a DT minority NN of IN studies NNS may MD be VB 21 CD . SENT However RB , , as IN discussed VVN in IN the DT next JJ section NN , , a DT number NN of IN methodologically RB adequate JJ association NN studies NNS of IN schizophrenia NN appear VVP to TO support VV the DT role NN of IN several JJ candidate NN genes NNS in IN the DT etiology NN of IN schizophrenia NN . SENT Similar JJ to TO the DT linkage NN study NN data NNS , , hard JJ replication NN remains VVZ elusive JJ . SENT Synthesis NN Despite IN the DT limitations NNS of IN the DT accumulated VVN linkage NN and CC association NN studies NNS , , there EX are VBP good JJ suggestions NNS that IN these DT studies NNS have VHP identified VVN plausible JJ candidate NN genes NNS for IN schizophrenia NN . SENT Table NN 2 CD summarizes VVZ the DT evidence NN in IN support NN of IN a DT set NN of IN possible JJ candidate NN genes NNS for IN schizophrenia NN . SENT Reports NNS supporting VVG the DT role NN of IN many JJ of IN these DT genes NNS have VHP appeared VVN in IN top JJ tier NN international JJ journals NNS known VVN for IN rigorous JJ peer NN review NN . SENT The DT evidence NN for IN several JJ genes NNS is VBZ encouraging VVG but CC currently RB insufficient JJ to TO declare VV any DT a DT clear JJ cut NN cause NN of IN schizophrenia NN . SENT Table NN 2 CD . SENT Evidence NN Supporting VVG 12 CD Potential JJ Candidate NN Genes NPS for IN SchizophreniaThe NP accumulated VVN data NNS provide VVP particular JJ support NN for IN DISC NN 1 CD , , DTNBP NP 1 CD , , NRG NP 1 CD , , and CC RGS NP 4 CD . SENT Each DT of IN these DT genes NNS has VHZ received VVN support NN from IN multiple JJ lines NNS of IN evidence NN with IN imperfect JJ consistency NN . SENT 1 LS The DT case NN for IN each DT of IN these DT as IN a DT candidate NN gene NN for IN schizophrenia NN is VBZ supported VVN by IN linkage NN studies NNS . SENT 2 LS The DT preponderance NN of IN association NN study NN findings NNS provides VVZ further JJR support NN . SENT 3 CD mRNA NN from IN each DT gene NN is VBZ expressed VVN in IN the DT prefrontal JJ cortex NN as IN well RB as RB in IN other JJ areas NNS of IN the DT brain NN . SENT and CC 4 CD Additional JJ neurobiological JJ data NNS link VVP the DT functions NNS of IN these DT genes NNS to TO biological JJ processes NNS thought VVD to TO be VB related VVN to TO schizophrenia NN . SENT For IN example NN , , DISC NN 1 CD modulates VVZ neurite NN outgrowth NN , , there EX is VBZ an DT extensive JJ literature NN on IN the DT involvement NN of IN NRG NP 1 CD in IN the DT development NN of IN the DT CNS NP , , and CC RGS NP 4 CD may MD modulate VV intracellular JJ signaling VVG for IN many JJ G NP protein NN coupled VVN receptors NNS . SENT Moreover RB , , DTNBP NP 1 CD and CC RGS NP 4 CD have VHP been VBN reported VVN to TO be VB differentially RB expressed VVN in IN postmortem JJ brain NN samples NNS of IN individuals NNS with IN schizophrenia NN . SENT This DT encouraging JJ summation NN of IN work NN in IN progress NN masks NNS a DT critical JJ issue NN the DT lack NN or CC consistent JJ replication NN for IN the DT same JJ markers NNS and CC haplotypes NNS across IN studies NNS . SENT The DT literature NN supports VVZ the DT contention NN that IN genetic JJ variation NN in IN these DT genes NNS is VBZ associated VVN with IN schizophrenia NN , , but CC it PP lacks VVZ impressive JJ consistency NN in IN the DT precise JJ genetic JJ regions NNS and CC alleles NNS implicated VVN . SENT In IN contrast NN , , association NN studies NNS of IN other JJ complex JJ human JJ genetic JJ diseases NNS have VHP produced VVN unambiguous JJ , , consistent JJ , , and CC clear JJ cut NN hard JJ replication NN . SENT For IN example NN , , 1 CD in IN Type NN 1 CD diabetes NN mellitus NN , , the DT bulk NN of IN both CC the DT linkage NN and CC association NN data NNS implicate VV the DT HLA NP region NN and CC INS NP 22 CD . SENT 2 CD for IN Type NN 2 CD diabetes NN mellitus NN , , there EX are VBP a DT number NN of IN findings NNS in IN the DT literature NN where WRB the DT association NN evidence NN appears VVZ to TO be VB consistent JJ and CC compelling JJ CAPN NP 10 CD , , KCNJ NP 11 CD , , and CC PPARG NP the DT data NNS indicate VVP that IN the DT same JJ marker NN allele NN is VBZ significantly RB associated VVN and CC has VHZ an DT effect NN size NN of IN similar JJ direction NN and CC magnitude NN 22 CD the DT linkage NN data NNS are VBP less RBR congruent JJ , , probably RB due JJ to TO power NN considerations NNS . SENT and CC 3 CD for IN age NN related VVN macular JJ degeneration NN , , at IN least JJS five CD studies NNS show VVP highly RB significant JJ association NN with IN the DT same JJ CFH NP Y NP 402 CD H NP polymorphism NN 23 CD 27 CD in IN a DT region NN strongly RB implicated VVN by IN multiple JJ linkage NN studies NNS . SENT For IN these DT findings NNS , , the DT data NNS are VBP highly RB compelling JJ and CC consistent JJ and CC provide VV a DT solid JJ foundation NN for IN the DT next JJ generation NN of IN studies NNS to TO investigate VV the DT mechanisms NNS of IN the DT gene NN phenotype NN connection NN . SENT Power NN type NN 2 CD error NN appears VVZ to TO be VB a DT major JJ factor NN if IN the DT genetic JJ effect NN is VBZ sufficiently RB large JJ HLA NP in IN Type NN 1 CD diabetes NN mellitus NN or CC CFH NP in IN age NN related VVN macular JJ degeneration NN or CC , , if IN the DT sample NN size NN is VBZ large JJ , , then RB there RB appears VVZ to TO be VB a DT greater JJR chance NN of IN hard JJ replication NN . SENT At IN present JJ , , the DT data NNS for IN schizophrenia NN are VBP confusing JJ , , and CC there EX are VBP two CD broad JJ possibilities NNS . SENT The DT first JJ possibility NN is VBZ that IN the DT current JJ findings NNS for IN some DT of IN the DT best JJS current JJ genes NNS are VBP true JJ . SENT This DT implies VVZ that IN the DT genetics NN of IN schizophrenia NN are VBP different JJ from IN other JJ complex JJ traits NNS in IN the DT existence NN of IN very RB high JJ degrees NNS of IN etiological JJ heterogeneity NN . SENT schizophrenia NN is VBZ hyper NN complex JJ , , and CC we PP need VVP to TO invoke VV more RBR complicated JJ genetic JJ models NNS than IN other JJ biomedical JJ disorders NNS . SENT The DT alternative JJ possibility NN is VBZ that IN the DT current JJ findings NNS are VBP clouded VVN by IN Type NN 1 CD and CC Type NN 2 CD error NN . SENT Schizophrenia NN is VBZ similar JJ to TO other JJ complex JJ traits NNS . SENT it PP is VBZ possible JJ that IN there EX are VBP kernels NNS of IN wheat NN , , but CC it PP is VBZ highly RB likely JJ that IN there EX is VBZ a DT lot NN of IN chaff NN . SENT At IN present JJ , , the DT second JJ and CC more RBR parsimonious JJ possibility NN has VHZ not RB been VBN rigorously RB excluded VVN . SENT The DT impact NN of IN Type NN 1 CD Type NN 2 CD error NN is VBZ likely JJ , , and CC it PP is VBZ not RB clear JJ why WRB schizophrenia NN should MD be VB inherently RB more RBR complex JJ . SENT At IN present JJ , , we PP cannot NN resolve VV these DT possibilities NNS . SENT Public NP Health NP Implications NNS The DT public JJ health NN importance NN of IN schizophrenia NN is VBZ clear JJ , , and CC the DT rationale NN for IN the DT search NN for IN genetic JJ causes NNS is VBZ strong JJ . SENT Schizophrenia NN research NN has VHZ never RB been VBN easy JJ . SENT the DT current JJ epoch NN of IN investigation NN into IN the DT genetics NN of IN schizophrenia NN provides VVZ a DT set NN of IN tantalizing VVG clues NNS , , but CC definitive JJ answers NNS are VBP not RB yet RB fully RB established VVN . SENT Findings NNS from IN the DT accumulated VVN literature NN appear VVP to TO be VB more JJR than IN chance NN yet RB sufficiently RB variable JJ as RB to TO render VV hard JJ replication NN elusive JJ . SENT The DT currently RB murky JJ view NN of IN this DT literature NN may MD result VV from IN the DT competing VVG filters NNS of IN Type NN 1 CD and CC Type NN 2 CD error NN . SENT The DT current JJ literature NN could MD be VB a DT mix NN of IN true JJ and CC false JJ positive JJ findings NNS . SENT however RB , , it PP would MD be VB a DT momentous JJ advance NN for IN the DT field NN if IN even RB one CD of IN the DT genes NNS in IN Table NN 2 CD were VBD a DT true JJ positive JJ result NN . SENT This DT body NN of IN work NN is VBZ not RB yet RB ready JJ for IN wholesale JJ translation NN into IN clinical JJ practice NN . SENT However RB , , it PP is VBZ not RB premature JJ to TO inform VV patients NNS that IN this DT work NN is VBZ advancing VVG and CC that WDT it PP holds VVZ promise NN for IN new JJ insights NNS into IN etiology NN , , pathophysiology NN , , and CC treatment NN on IN the DT five CD to TO ten CD year NN horizon NN . SENT On IN a DT larger JJR scale NN , , the DT treatment NN of IN the DT mentally RB ill JJ mirrors VVZ the DT humanity NN of IN a DT society NN . SENT in IN many JJ societies NNS , , the DT return NN image NN is VBZ not RB flattering VVG . SENT If IN a DT specific JJ genetic JJ variation NN were VBD proven VVN to TO be VB causal JJ to TO schizophrenia NN , , this DT poor JJ reflection NN might MD improve VV 28 CD . SENT GLOSSARY NN Multiplex NN pedigree NN . SENT A DT family NN grouping NN of IN genetically RB related VVN individuals NNS with IN multiple JJ affected JJ individuals NNS . SENT First JJ stage NN genome NN scan VV . SENT An DT initial JJ survey NN of IN the DT genome NN to TO identify VV regions NNS that WDT may MD contain VV genetic JJ variants NNS that WDT could MD cause VV the DT disease NN under IN study NN . SENT Subsequent JJ stages NNS focus VVP on IN a DT smaller JJR genomic JJ region NN . SENT Type NN 1 CD error NN . SENT The DT probability NN of IN rejecting VVG a DT true JJ null NN hypothesis NN akin JJ to TO a DT false JJ positive JJ result NN . SENT Type NN 2 CD error NN . SENT The DT probability NN of IN accepting VVG a DT false JJ null NN hypothesis NN akin JJ to TO a DT false JJ negative JJ result NN . SENT ReferencesSaha NP S NP , , Welham NP J NP , , Chant NP D NP , , McGrath NP J NP 2005 CD The DT epidemiology NN of IN schizophrenia NN . SENT PLoS NP Med NP 2 CD . SENT e SYM 141 CD . SENT Find VV this DT article NN onlineMcGlashan NN TH NN 1988 CD A DT selective JJ review NN of IN recent JJ North NP American NP long JJ term NN followup NN studies NNS of IN schizophrenia NN . SENT Schizophr NP Bull NP 14 CD . SENT 515 CD 542 CD . SENT Find VV this DT article NN onlineMurray NN CJL NP , , Lozpe NP AD NN 1996 CD The DT global JJ burden NN of IN disease NN . SENT A DT comprehensive JJ assessment NN of IN mortality NN and CC disability NN from IN diseases NNS , , injuries NNS , , and CC risk NN factors NNS in IN 1990 CD and CC projected VVD to TO 2020 CD . SENT Boston NP . SENT Harvard NP University NP Press NP . SENT 900 CD p NN . SENT Jeste NP DV NP , , Gladsjo NP JA NP , , Lindamer NP LA NP , , Lacro NP JP NP 1996 CD Medical NP comorbidity NN in IN schizophrenia NN . SENT Schizophr NP Bull NP 22 CD . SENT 413 CD 430 CD . SENT Find VV this DT article NN onlineHarris NN EC NP , , Barraclough NP BB NP 1998 CD Excess JJ mortality NN of IN mental JJ disorder NN . SENT Br NP J NP Psychiatry NP 173 CD . SENT 11 CD 53 CD . SENT Find VV this DT article NN onlineMurray NN RM NP , , Jones NP PB NP , , Susser NP E NP , , van NN Os NN J NP , , Cannon NP M NP 2003 CD The DT epidemiology NN of IN schizophrenia NN . SENT Cambridge NP . SENT Cambridge NP University NP Press NP . SENT 470 CD p NN . SENT Mortensen NP PB NP , , Pedersen NP CB NP , , Westergaard NP T NN , , Wohlfahrt NP J NP , , Ewald NP H NP , , et NP al NP . SENT 1999 CD Effects NNS of IN family NN history NN and CC place NN and CC season NN of IN birth NN on IN the DT risk NN of IN schizophrenia NN . SENT N NP Engl NP J NP Med NP 340 CD . SENT 603 CD 608 CD . SENT Find VV this DT article NN onlinePlomin NN R NN , , DeFries NP JC NP , , Craig NP IW NP , , McGuffin NP P NN 2003 CD Behavioral JJ genetics NNS in IN the DT postgenomic JJ era NN , , 3 CD rd NNS ed NP . SENT Washington NP , , DC NP . SENT APA NP Books NPS . SENT 414 CD p NN . SENT Sullivan NP PF NP , , Kendler NP KS NP , , Neale NP MC NP 2003 CD Schizophrenia NN as IN a DT complex JJ trait NN . SENT Evidence NN from IN a DT meta NP analysis NN of IN twin JJ studies NNS . SENT Arch NP Gen NP Psychiatry NP 60 CD . SENT 1187 CD 1192 CD . SENT Find VV this DT article NN onlineSullivan NN PF NP , , Owen NP MJ NP , , ODonovan NP MC NP , , Freedman NP RR NP , , 2005 CD Genetics NP . SENT In IN . SENT Lieberman NP J NP , , Stroup NP T NN , , Perkins NP D NP , , editors NNS . SENT Textbook NN of IN schizophrenia NN Washington NP , , DC NP . SENT American JJ Psychiatric JJ Publishing NN . SENT In IN press NN . SENT Korstanje NP R NP , , Paigen NP B NP 2002 CD From IN QTL NP to TO gene NN . SENT The DT harvest NN begins VVZ . SENT Nat NP Genet NP 31 CD . SENT 235 CD 236 CD . SENT Find VV this DT article NN onlineLewis NN CM NP , , Levinson NP DF NP , , Wise NP LH NP , , DeLisi NP LE FW , , Straub NP RE NN , , et NP al NP . SENT 2003 CD Genome NN scan VV meta NP analysis NN of IN schizophrenia NN and CC bipolar JJ disorder NN , , part NN II NP . SENT Schizophrenia NN . SENT Am NP J NP Hum NP Genet NP 73 CD . SENT 34 CD 48 CD . SENT Find VV this DT article NN onlineStraub NN RE NN , , MacLean NP CJ NP , , ONeill NP FA NN , , Burke NP J NP , , Murphy NP B NP , , et NP al NP . SENT 1995 CD A NP potential JJ vulnerability NN locus NN for IN schizophrenia NN on IN chromosome NN 6 CD p NN 24 CD 22 CD . SENT Evidence NN for IN genetic JJ heterogeneity NN . SENT Nat NP Genet NP 11 CD . SENT 287 CD 293 CD . SENT Find VV this DT article NN onlineSchwab NN SG NP , , Hallmayer NP J NP , , Albus NP M NP , , Lerer NP B NP , , Eckstein NP GN NP , , et NP al NP . SENT 2000 CD A NP genome NN wide JJ autosomal JJ screen NN for IN schizophrenia NN susceptibility NN loci NNS in IN 71 CD families NNS with IN affected JJ siblings NNS . SENT Support NN for IN loci NNS on IN chromosome NN 10 CD p NN and CC 6 CD . SENT Mol NP Psychiatry NP 5 CD . SENT 638 CD 649 CD . SENT Find VV this DT article NN onlineMoises VVZ HW NP , , Yang NP L NP , , Kristbjarnarson NP H NP , , Wiese NP C NP , , Byerley NP W NP , , et NP al NP . SENT 1995 RB An DT international JJ two CD stage NN genome NN wide JJ search NN for IN schizophrenia NN susceptibility NN genes NNS . SENT Nat NP Genet NP 11 CD . SENT 321 CD 324 CD . SENT Find VV this DT article NN onlineMaziade NN M NP , , Roy NP MA NN , , Rouillard NP E NP , , Bissonnette NP L NP , , Fournier NP JP NP , , et NP al NP . SENT 2001 CD A DT search NN for IN specific JJ and CC common JJ susceptibility NN loci NNS for IN schizophrenia NN and CC bipolar JJ disorder NN . SENT A DT linkage NN study NN in IN 13 CD target NN chromosomes NNS . SENT Mol NP Psychiatry NP 6 CD . SENT 684 CD 693 CD . SENT Find VV this DT article NN onlineLindholm NP E NP , , Ekholm NP B NP , , Shaw NP S NP , , Jalonen NP P NN , , Johansson NP G NP , , et NP al NP . SENT 2001 CD A NP schizophrenia NN susceptibility NN locus NN at IN 6 CD q NN 25 CD , , in IN one CD of IN the DT world's JJ largest JJS reported VVN pedigrees NNS . SENT Am NP J NP Hum NP Genet NP 69 CD . SENT 96 CD 105 CD . SENT Find VV this DT article NN onlineSchizophrenia NN Linkage NN . SENT Collaborative JJ Group NP 1996 CD Additional JJ support NN for IN schizophrenia NN linkage NN on IN chromosomes NNS 6 CD and CC 8 CD . SENT A DT multicenter NN study NN . SENT Schizophrenia NN Linkage NN Collaborative JJ Group NP for IN Chromosomes NNS 3 CD , , 6 CD and CC 8 CD . SENT Am NP J NP Med NP Genet NP 67 CD . SENT 580 CD 594 CD . SENT Find VV this DT article NN onlineSullivan NN PF NP , , Eaves NP LJ NP , , Kendler NP KS NP , , Neale NP MC NP 2001 CD Genetic NP case NN control NN association NN studies NNS in IN neuropsychiatry NN . SENT Arch NP Gen NP Psychiatry NP 58 CD . SENT 1015 CD 1024 CD . SENT Find VV this DT article NN onlineFan NN JB NP , , Zhang NP CS NP , , Gu NP NF NP , , Li NP XW NP , , Sun NP WW NP , , et NP al NP . SENT 2005 CD Catechol NN O NN methyltransferase NN gene NN Val NP Met NP functional JJ polymorphism NN and CC risk NN of IN schizophrenia NN . SENT A DT large JJ scale NN association NN study NN plus IN meta NP analysis NN . SENT Biol NP Psychiatry NP 57 CD . SENT 139 CD 144 CD . SENT Find VV this DT article NN onlineShifman NN S NP , , Bronstein NP M NP , , Sternfeld NP M NP , , Pisante NP Shalom NP A NP , , Lev NP Lehman NP E NP , , et NP al NP . SENT 2002 CD A DT highly RB significant JJ association NN between IN a DT COMT NP haplotype NN and CC schizophrenia NN . SENT Am NP J NP Hum NP Genet NP 71 CD . SENT 1296 CD 1302 CD . SENT Find VV this DT article NN onlineFlorez NP JC NP , , Hirschhorn NP J NP , , Altshuler NP D NP 2003 CD The DT inherited VVN basis NN of IN diabetes NN mellitus NN . SENT Implications NNS for IN the DT genetic JJ analysis NN of IN complex JJ traits NNS . SENT Annu NP Rev NP Genomics NP Hum NP Genet NP 4 CD . SENT 257 CD 291 CD . SENT Find VV this DT article NN onlineKlein NN RJ NP , , Zeiss NP C NP , , Chew NP EY NP , , Tsai NP JY NP , , Sackler NP RS NP , , et NP al NP . SENT 2005 CD Complement NN factor NN H NN polymorphism NN in IN age NN related VVN macular JJ degeneration NN . SENT Science NP 308 CD . SENT 385 CD 389 CD . SENT Find VV this DT article NN onlineZareparsi NP S NP , , Branham NP KE NP , , Li NP M NP , , Shah NP S NP , , Klein NP RJ NP , , et NP al NP . SENT 2005 CD Strong JJ association NN of IN the DT Y NP 402 CD H NN variant NN in IN complement VV factor NN H NN at IN 1 CD q NN 32 CD with IN susceptibility NN to TO age NN related JJ macular JJ degeneration NN . SENT Am NP J NP Hum NP Genet NP 77 CD . SENT 149 CD 153 CD . SENT Find VV this DT article NN onlineHageman NN GS NP , , Anderson NP DH NP , , Johnson NP LV NP , , Hancox NP LS NP , , Taiber NP AJ NP , , et NP al NP . SENT 2005 CD From IN the DT cover NN . SENT A DT common JJ haplotype NN in IN the DT complement VV regulatory JJ gene NN factor NN H NP HF NP 1 CD CFH NP predisposes VVZ individuals NNS to TO age NN related JJ macular JJ degeneration NN . SENT Proc NP Natl NP Acad NP Sci NP U NP S NP A NP 102 CD . SENT 7227 CD 7232 CD . SENT Find VV this DT article NN onlineEdwards NNS AO NP , , Ritter NP R NP III NP , , Abel NP KJ NP , , Manning NP A NP , , Panhuysen NP C NP , , et NP al NP . SENT 2005 CD Complement NN factor NN H NN polymorphism NN and CC age NN related VVN macular JJ degeneration NN . SENT Science NP 308 CD . SENT 421 CD 424 CD . SENT Find VV this DT article NN onlineHaines NNS JL NP , , Hauser NP MA NN , , Schmidt NP S NP , , Scott NP WK NP , , Olson NP LM NP , , et NP al NP . SENT 2005 CD Complement NN factor NN H NN variant NN increases VVZ the DT risk NN of IN age NN related VVN macular JJ degeneration NN . SENT Science NP 308 CD . SENT 419 CD 421 CD . SENT Find VV this DT article NN onlineBraslow NN JT NP 1995 CD Effect NN of IN therapeutic JJ innovation NN on IN perception NN of IN disease NN and CC the DT doctor NN patient NN relationship NN . SENT A DT history NN of IN general JJ paralysis NN of IN the DT insane JJ and CC malaria NN fever NN therapy NN , , 1910 CD 1950 CD . SENT Am NP J NP Psychiatry NP 152 CD . SENT 660 CD 665 CD . SENT Find VV this DT article NN online JJ View NN this DT article NN by IN . SENT FiguresTablesPrint NP PDF NP 1088 CD K NP Screen NP PDF NP 303 CD K NP Download NP CitationDownload NP XML NP Options NPS . SENT See VV Articles NNS Citing VVG This DT ArticleE NP mail NN this DT ArticleSend NP Us NP an DT eLetterRead JJ Other JJ eLettersSearch NN PubMed VVN for IN . SENT Patrick NP F NP . SENT Sullivan NP PLoS NP Medicine NP is VBZ an DT open JJ access NN journal NN published VVN by IN the DT nonprofit JJ organization NN Public JJ Library NN of IN Science NP . SENT All DT journal NN content NN , , except IN where WRB otherwise RB noted VVN , , is VBZ licensed VVN under IN a DT Creative JJ Commons NP Attribution NN License NN . SENT