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HEALTH

ScientistsMoveCloserto
UnderstandingSchizophreniasCause
ByBENEDICTCAREY

JAN.27,2016

ScientistsreportedonWednesdaythattheyhadtakenasignificantstep
towardunderstandingthecauseofschizophrenia,inalandmarkstudythat
providesthefirstrigorouslytestedinsightintothebiologybehindany
commonpsychiatricdisorder.
MorethantwomillionAmericanshaveadiagnosisofschizophrenia,
whichischaracterizedbydelusionalthinkingandhallucinations.Thedrugs
availabletotreatitbluntsomeofitssymptomsbutdonottouchthe
underlyingcause.
Thefinding,publishedinthejournalNature,willnotleadtonew
treatmentssoon,expertssaid,nortowidelyavailabletestingforindividual
risk.Buttheresultsprovideresearcherswiththeirfirstbiologicalhandleon
anancientdisorderwhosecausehasconfoundedmodernsciencefor
generations.Thefindingalsohelpsexplainsomeothermysteries,including
whythedisorderoftenbeginsinadolescenceoryoungadulthood.
Theydidaphenomenaljob,saidDavidB.Goldstein,aprofessorof
geneticsatColumbiaUniversitywhohasbeencriticalofpreviouslarge
scaleprojectsfocusedonthegeneticsofpsychiatricdisorders.Thispaper
givesusafoothold,somethingwecanworkon,andthatswhatwevebeen
lookingfornow,foralong,longtime.

Theresearcherspiecedtogetherthestepsbywhichgenescanincrease
apersonsriskofdevelopingschizophrenia.Thatrisk,theyfound,istiedto
anaturalprocesscalledsynapticpruning,inwhichthebrainshedsweakor
redundantconnectionsbetweenneuronsasitmatures.Duringadolescence
andearlyadulthood,thisactivitytakesplaceprimarilyinthesectionofthe
brainwherethinkingandplanningskillsarecentered,knownasthe
prefrontalcortex.Peoplewhocarrygenesthataccelerateorintensifythat
pruningareathigherriskofdevelopingschizophreniathanthosewhodo
not,thenewstudysuggests.
Someresearchershadsuspectedthatthepruningmustsomehowgo
awryinpeoplewithschizophrenia,becausepreviousstudiesshowedthat
theirprefrontalareastendedtohaveadiminishednumberofneural
connections,comparedwiththoseofunaffectedpeople.Thenewpapernot
onlystronglysupportsthatthisisthecase,butalsodescribeshowthe
pruningprobablygoeswrongandwhy,andidentifiesthegenes
responsible:Peoplewithschizophreniahaveagenevariantthatapparently
facilitatesaggressivetaggingofconnectionsforpruning,ineffect
acceleratingtheprocess.
Somescientistswarnedthatthehistoryofbiologicalpsychiatrystands
asacautionagainstprematureoptimism.Thisworkisextremely
persuasive,saidDr.SamuelBarondes,aprofessorofpsychiatryatthe
UniversityofCalifornia,SanFrancisco,butanystepforwardisnotonly
rareandunusual,itsjustonestepinajourneyofathousandmilesto
improvedtreatments.
Thestudy,byscientistsfromHarvardMedicalSchool,Boston
ChildrensHospitalandtheBroadInstitute,aresearchcenteralliedwith
HarvardandtheMassachusettsInstituteofTechnology,providesa
showcaseofbiomedicalinvestigationatitshighestlevel.Theresearchteam
beganbyfocusingonalocationonthehumangenome,theMHC,which
wasmoststronglyassociatedwithschizophreniainpreviousgenetic
studies.OnabargraphcalledaManhattanplotbecauseitlookslikea
clusterofskyscraperstheMHCloomshighest.

TheMHCistheFreedomToweroftheManhattanplot,saidEricS.
Lander,thedirectoroftheBroadInstitute.Thequestionwas,whatsin
there?
Theareaisanotoriouslydarkwarreninthegenomeknowntocontain
genesthatfacilitatethebodysimmuneresponse,forexample,byflagging
invadingbacteriatobedestroyed.Thatpropertyhadgivenriseto
speculationthatschizophreniamightbeakindofautoimmunecondition,
inwhichthebodyattackeditsowncells.
Buttheresearchteam,ledbyStevenMcCarroll,anassociateprofessor
ofgeneticsatHarvard,andbyAswinSekar,oneofhisgraduatestudents,
foundsomethingdifferent.Usingadvancedstatisticalmethods,theteam
foundthattheMHClocuscontainedfourcommonvariantsofagenecalled
C4,andthatthosevariantsproducedtwokindsofproteins,C4AandC4B.
Theteamanalyzedthegenomesofmorethan64,000peopleandfound
thatpeoplewithschizophreniaweremorelikelytohavetheoveractive
formsofC4Athancontrolsubjects.C4Aseemedtobethegenedriving
riskforschizophrenia,Dr.McCarrollsaid,butwehadtobesure.
TheresearchersturnedtoBethStevens,anassistantprofessorof
neurologyatBostonChildrensHospitalandHarvard,whowasanauthorof
a2007studyshowingthattheproductsofMHCgeneswereinvolvedin
synapticpruninginnormaldevelopingbrains.Buthowimportantwasthis
C4protein,exactly?Veryimportant,itturnedout:Micebredwithoutthe
genesthatproduceC4showedclearsignsthattheirsynapticpruninghad
goneawry,Dr.Stevensslabfound.
Takentogether,Dr.Stevenssaidinaninterview,theevidencestrongly
suggestedthattoomuchC4Aleadstoinappropriatepruningduringthis
criticalphaseofdevelopment.
Inparticular,theauthorsconcluded,toomuchC4Acouldmeantoo
muchpruningwhichwouldexplainnotonlythethinnerprefrontallayers
inschizophrenia,butalsothereasonthatthedisordermostoftenshows

itselfinpeoplesteenageyearsorearlytwenties.Thefindingconnectsall
thesedots,allthesedisconnectedobservationsaboutschizophrenia,and
makesthemmakesense,Dr.McCarrollsaid.
Carryingagenevariantthatfacilitatesaggressivepruningishardly
enoughtocauseschizophreniafartoomanyotherfactorsareatwork.
Havingsuchavariant,Dr.McCarrollestimates,wouldincreaseapersons
riskbyabout25percentoverthe1percentbaserateofschizophrenia
thatis,to1.25percent.Thatisnotnearlyenoughtojustifytestinginthe
generalpopulation,eveniffurtherresearchconfirmsthenewfindingsand
clarifiestherolesofotherassociatedgenes.
Yettheequationchangeswhenitcomestoyoungpeoplewhoareat
veryhighriskofdevelopingthedisorder,becausetheyareshowingearly
signsasuddenslippageinmentalacuityandmemory,oreveninternal
voicesthatseemoddlyreal.Thisominousperiodmaylastayearormore,
andoftendoesnotleadtofullblownschizophrenia.Theresearchershope
thattheatriskgeneticprofile,onceithasbeenfleshedoutmore
completely,willleadtothediscoveryofbiomarkersthatcouldhelpclarifya
prognosisinthesepeople.
Developingadrugtoslowormodulatepruningposesanotherkindof
challenge.Ifthenewstudyshowsanything,itisthatsynapticpruningisa
delicate,exquisitelytimedprocess,andthatitisstillpoorlyunderstood.
Theteamdoesnotyetknow,forexample,whyC4Aleadstoadifferentrate
orkindofpruningthanC4B.Anymedicationthattamperedwiththat
systemwouldbeariskyproposition,theauthorsandoutsideexperts
agreed.
Wereallveryexcitedandproudofthiswork,Dr.Landersaid.But
Imnotreadytocallitavictoryuntilwehavesomethingthatcanhelp
patients.
AversionofthisarticleappearsinprintonJanuary28,2016,onpageA1oftheNewYork
editionwiththeheadline:ScientistsHomeInonCauseofSchizophrenia.

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