BehavioralSystemsCognitive Genetic Contributions to Human Br

Variation in gray matter (GM) and white matter (WM) volume of the adult human brain is primarily genetically determined. Moreover, total brain volume is positively correlated with general intelligence, and both share a common genetic origin. However, altho

TheJournalofNeuroscience,October4,2006 26(40):10235–10242 10235

Behavioral/Systems/Cognitive

GeneticContributionstoHumanBrainMorphologyandIntelligence

HillekeE.HulshoffPol,1HugoG.Schnack,1DaniellePosthuma,2Rene´C.W.Mandl,1WimF.Baare´,1ClarinevanOel,1NeeltjeE.vanHaren,1D.LouisCollins,3AlanC.Evans,3KatrinAmunts,4,5UliBu¨rgel,6,7KarlZilles,4,7EcodeGeus,2DorretI.Boomsma,2andRene´S.Kahn1

DepartmentofPsychiatry,RudolfMagnusInstituteofNeuroscience,UniversityMedicalCenterUtrecht,3584CXUtrecht,TheNetherlands,2DepartmentofBiologicalPsychology,FreeUniversityAmsterdam,1081BTAmsterdam,TheNetherlands,3MontrealNeurologicalInstitute,McGillUniversity,

Montreal,Quebec,Canada,H3A2B4,4InstitutfuerMedizin,ForschungszentrumJuelich,D-52405Juelich,Germany,Departmentsof5PsychotherapyandPsychiatryand6Neurosurgery,DieLeitseitederRheinisch-Westfa¨lischenTechnischenHochschuleAachenUniversity,D-52062Aachen,Germany,and7C.andO.VogtInstituteforBrainResearch,HeineUniversityDu¨sseldorf,D-40225Du¨sseldorf,Germany

1

Variationingraymatter(GM)andwhitematter(WM)volumeoftheadulthumanbrainisprimarilygeneticallydetermined.Moreover,totalbrainvolumeispositivelycorrelatedwithgeneralintelligence,andbothshareacommongeneticorigin.However,althoughgeneticeffectsonmorphologyofspecificGMareasinthebrainhavebeenstudied,theheritabilityoffocalWMisunknown.Similarly,itisunresolvedwhetherthereisacommongeneticoriginoffocalGMandWMstructureswithintelligence.WeexploredthegeneticinfluenceonfocalGMandWMdensitiesinmagneticresonancebrainimagesof54monozygoticand58dizygotictwinpairsand34oftheirsiblings.Forgeneticanalyses,weusedstructuralequationmodelingandvoxel-basedmorphometry.ToexplorethecommongeneticoriginoffocalGMandWMareaswithintelligence,weobtainedcross-trait/cross-twincorrelationsinwhichthefocalGMandWMdensitiesofeachtwinarecorrelatedwiththepsychometricintelligencequotientofhis/hercotwin.Genesinfluencedinpidualdifferencesinleftandrightsuperioroccipitofrontalfascicle(heritabilityupto0.79and0.77),corpuscallosum(0.82,0.80),opticradiation(0.69,0.79),corticospinaltract(0.78,0.79),medialfrontalcortex(0.78,0.83),superiorfrontalcortex(0.76,0.80),superiortemporalcortex(0.80,0.77),leftoccipitalcortex(0.85),leftpostcentralcortex(0.83),leftposteriorcingulatecortex(0.83),rightparahippocampalcortex(0.69),andamygdala(0.80,0.55).Intelligencesharedacommongeneticoriginwithsuperioroccipitofrontal,callosal,andleftopticalradiationWMandfrontal,occipital,andparahippocam-palGM(phenotypiccorrelationsupto0.35).Thesefindingspointtoaneuralnetworkthatsharesacommongeneticoriginwithhumanintelligence.

Keywords:genetics;twins;neuroanatomy;voxel-basedmorphometry;intelligence;cognition

Introduction

Variationintotalgrayandwhitemattervolumeoftheadulthumanbrainisprimarily(70–80%)geneticallydetermined(Penningtonetal.,2000;Pfefferbaumetal.,2000;Baare´etal.,2001).Moreover,totalbrainvolumeispositivelycorrelatedwithgeneralintelligence,andbothshareacommongeneticorigin(Posthumaetal.,2002).However,thisfindingdoesnotnecessar-ilymeanthatgenesinfluencefocalbrainstructuresinthesamemannerthroughoutthebrain.Moreover,itdoesnotnecessarily

ReceivedOct.11,2005;revisedJuly20,2006;acceptedJuly21,2006.

ThisworkwassupportedinpartbyNetherlandsOrganizationforScientificResearch/NetherlandsOrganizationforHealthResearchandDevelopmentVIDIProgramGrant917.46.370(H.E.H.),theFederationforEuropeanNeuro-scienceSocieties(H.E.H),theHumanFrontiersScienceProgramGrantrg0154/1998-B(D.I.B.),andtheUniversitairStimuleringsFonds(D.I.B.).ThisHumanBrainProject/NeuroinformaticsresearchisfundedbytheNationalInstituteofBiomedicalImagingandBioengineering,theNationalInstituteofNeurologicalDisordersandStroke,andtheNationalInstituteofMentalHealth(K.Z.,K.A.).AdditionalsupportbytheBrainImagingCenterWest(Bundesmin-isteriumfu¨rBildungundForschungGrant01GO0204)isgratefullyacknowledged(K.Z.).

CorrespondenceshouldbeaddressedtoDr.HillekeE.HulshoffPol,UniversityMedicalCenterUtrecht,Heidelber-glaan100,DepartmentofPsychiatry,A01.126,3584CXUtrecht,TheNetherlands.E-mail:h.e.hulshoff@azu.nl.Partsofthisworkhavebeenpresentedpreviouslyatthe34thAnnualMeetingoftheSocietyforNeuroscience,SanDiego,CA,October23–27,2004.DOI:10.1523/JNEUROSCI.1312-06.2006

Copyright©2006SocietyforNeuroscience0270-6474/06/2610235-08$15.00/0

meanthatacommongeneticoriginwithgeneralintelligenceissharedbyallstructuresthroughoutthebrain.

Determiningtheextenttowhichfocalbrainmorphologyanditsassociationwithcognitivefunctioningareinfluencedbygenes(orenvironment)isimportantforbothourunderstandingofhealthyfunctioningandelucidatingthecausesofbraindisease.Morespecifically,itenhancesourknowledgeofinpidualvari-ationinbrainfunctioningandaidsintheinterpretationofthemorphologicalchangesasfoundinpsychiatricdisorderssuchasschizophrenia.Also,itallowsfutureeffortstofindparticulargenesresponsibleforbrainstructuresandfunctionstobecon-centratedonbrainareasthatareunderconsiderablegeneticinfluence.

Todate,moststudiesfocusedonthegeneticinfluenceonvariationintotalbrainvolume.Afewstudieshaveexaminedgeneticeffectsonmorespecificbrainareasthroughoutthebrain.Morphologyoffocalfrontalandtemporalgraymatter(GM)ar-easisparticularlyinfluencedbygeneticfactors(Thompsonetal.,2001;Wrightetal.,2002).However,thegeneticinfluenceonfocalwhitematter(WM)hasnotbeenexamined.IthasbeensuggestedthatfrontalGMvolumeandintelligencesharegeneticfactors,butitalsoremainsunresolvedwhetherthisassociation

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