Cortical Mapping of Genotype Phenotype Relationships in Schizophrenia

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1 Human Bain Mapping 28: (2007) Cotical Mapping of Genotype Phenotype Relationships in Schizophenia Caie E. Beaden, 1 * Theo G.M. van Ep, 2 Paul M. Thompson, 3 Athu W. Toga, 3 and Tyone D. Cannon 1,2 1 Depatment of Psychiaty and Biobehavioal Sciences, Semel Institute fo Neuoscience and Human Behavio, Univesity of Califonia, Los Angeles, Califonia 2 Depatment of Psychology, Univesity of Califonia, Los Angeles, Califonia 3 Depatment of Neuology, Laboatoy of Neuo Imaging, Univesity of Califonia, Los Angeles, Califonia Abstact: Although schizophenia is highly heitable, the seach fo susceptibility genes has been challenging. The endophenotype appoach is an altenative method fo measuing phenotypic vaiation that may make it easie to identify susceptibility genes in the context of complexly inheited taits. Neuoimaging methods in paticula offe a poweful way to bidge the neuobiology of genes and behavio. Such investigations may be futhe empoweed by complementay stategies involving chomosomal abnomalities associated with schizophenia, which can help to localize causative genes and bette undestand the genetic complexity of the illness. Hee, we illustate ou use of these convegent appoaches, with a focus on neuoimaging studies using novel computational bain mapping algoithms, to investigate genetic influences on bain stuctue in the development of psychosis. These studies povide compelling evidence that specific genetic loci suspected to pedispose to schizophenia may affect quantitative vaiation in neual indicatos undelying the neuobehavioal phenotype, and illustate how genetic-neuoimaging paadigms can impove ou undestanding of the pathogenesis of this highly disabling mental illness. Hum Bain Mapp 28: , VC 2007 Wiley-Liss, Inc. Key wods: psychosis; bain mapping; genetic; neuoanatomy; chomosome 22q11.2; velocadiofacial syndome; twin study; DISC1 INTRODUCTION Schizophenia is one of the most chonic and debilitating of psychiatic syndomes and, with a lifetime pevalence The authos have no conflicts of inteest to declae. Contact gant sponso: National Institute of Mental Health; Contact gant numbes: K23 MH (C.E.B.), R01 MH52857 (T.D.C.); Contact gant sponso: Cente fo Computational Biology (CCB); Contact gant numbe: U54 RR021813; Contact gant sponso: NIH/ NCRR; Contact gant numbe: P41 RR013642; Contact gant sponso: National Institute fo Biomedical Imaging and Bioengineeing; Contact gant numbe: EB01651; Contact gant sponso: National Cente fo Reseach Resouces; Contact gant numbe: RR019771; Contact gant sponso: National Institute on Aging; Contact gant numbe: AG016570; Contact gant sponso: National Libay of Medicine; Contact gant numbe: LM05639; Contact gant sponso: National Institute fo Neuological Disodes and Stoke; Contact gant numbe: of about 1%, it epesents a majo public health concen. Despite the vey high heitability fo this disode [80 85%; Cadno et al., 1999; McGuffin et al. 1984], the seach fo schizophenia susceptibility genes has been slow to NS049194; Contact gant sponso: National Institute fo Child Health and Human Development; Contact gant numbe: HD050735; Contact gant sponso: NIH (NIH Roadmap fo Medical Reseach) *Coespondence to: Caie E. Beaden, Ph.D., Depatment of Psychiaty and Biobehavioal Sciences, Univesity of Califonia, Los Angeles, 300 Building Medical Plaza, Suite 2265, Los Angeles, Califonia cbeaden@mednet.ucla.edu Received fo publication 4 Decembe 2006; Revision 22 Febuay 2007; Accepted 5 Mach 2007 DOI: /hbm Published online 16 Apil 2007 in Wiley InteScience (www. intescience.wiley.com). VC 2007 Wiley-Liss, Inc.

2 Beaden et al. Figue 1. Schematic of convegent stategies fo investigating schizophenia endophenotypes: Common genes of small effect and ae genetic mutations of high penetance may esult in shaed/ovelapping neuoanatomic featues. pogess. Studies of the inheitance of schizophenia have evealed that it is in geneal a complex and multifactoial disode, likely involving multiple genes of small effect that each contibute a modest degee of isk and, possibly in combination with envionmental factos, influence numeous cental nevous system taits. Howeve, thee ae, in addition, cetain neuogenetic conditions, which confe substantially elevated isk fo schizophenia, and may theefoe epesent a specific, moe homogeneous subtype of the illness, with well-chaacteized genetic etiology. Ou appoach to elucidating the natue of gene-bainbehavio linkages in complex neuopsychiatic disodes such as schizophenia is based on the pemise that these diseases ae best conceptualized as sets of quantitative taits that eflect intemediate phenotypes between pedisposing genes and syndomal expession [ endophenotypes ; Gottesman and Gould, 2003]. Given that nealy half of all genes ae expessed in the bain [Sandbeg et al., 2000], and bain stuctue volumes ae highly heitable [Camelli et al., 1998; Pfeffebaum et al., 2000; Posthuma et al., 2000], neuoanatomic phenotypes offe a compelling altenative to categoically defined disease syndomes. It is ou hypothesis that many of these genes contibute to schizophenia susceptibility though thei impact on bain systems involved in motivational, attentional, and memoy pocesses, and that most of these genes have been undetected by pevious studies that have examined syndomal status as the phenotypic taget. Hee, we descibe ou use of conveging methods to investigate genetic influences on bain stuctue in the development of psychosis: (1) Concodant and discodant twin studies, which allow us to identify heitable dimensions of CNS pathology in schizophenia, and (2) Studies of possible genetic subtypes of the disease with vey high penetance (i.e., 22q11.2 micodeletions). Heitability of Bain Stuctue in Nomal Twins Neuobehavioal phenotypes develop as a esult of complex aggegations of, and inteactions between, sets of genes impacting paticula neual pathways and envionmental cicumstances that modify the expession of those genes as well as the development and functioning of those pathways. Twin studies can be used to disentangle genetic fom shaed and unique envionmental effects, allowing fo the identification of quantitative neuodevelopmental phenotypes that ae heitable in the geneal population. Pio wok using taditional volumetic appoaches has shown high heitabilities fo majo neuoanatomic featues [Baae et al., 2001; Batley et al., 1997; Biondi et al., 1998; Camelli et al., 1998; Geschwind et al., 2002; Oppenheim et al., 1989; Pennington et al., 2000; Pfeffebaum et al., 2000, 2001; Posthuma et al., 2000; Scamvougeas et al., 2003; Sullivan et al., 2001; Thompson et al., 2001, 2004; Tamo et al., 1998; White et al., 2002; Wight et al., 2002]. Based on vaiance component analyses, additive genetic influences appea to account fo 52 91% of the total vaiance in intacanial volume [Camelli et al., 1998; Pfeffebaum et al., 2000; Posthuma et al., 2000], 62 94% fo total bain volume [Batley et al., 1997; Camelli et al., 1998; Wight et al., 2002], 82 87% fo gay and white matte volumes [Baae et al., 2001], 40 69% fo hippocampal volume [Sullivan et al., 2001], and 79 94% fo copus callosum aeas [Pfeffebaum et al., 2000; Scamvougeas et al., 2003]. Howeve, because many aspects of cotical suface geomety 520

3 Genotype-Phenotype Mapping in Schizophenia diffe between individuals, and even between pais of genetically identical cotwins, quantification techniques that do not account fo individual diffeences in these featues may be misleading. Thus, a key element of ou stategy is the use of computational methods fo cotical suface modeling and cotical patten matching, to aggegate imaging datasets in the same anatomic efeence locations acoss subjects (as in [Thompson et al., 2004]). These algoithms ae exquisitely sensitive to vaiation in egional tissue densities and othe neual featues of inteest, because homologous sulcal landmaks ae in pefect alignment acoss subjects. Powe is geatly inceased as the esidual anatomic vaiability is diectly modeled, and confounding vaiations ae factoed out befoe betweengoup compaisons ae made. Simila cotical mapping appoaches have been applied by othe goups developing methods to visualize cotical data [Fischl and Dale, 2000; Hudal and Stephenson, 2004; Van Essen, 2004]. Using these methods, we ceated the fist cotical maps of genetic influences on human bain stuctue in twins [Thompson et al., 2001] (Fig. 2). Ou sample consisted of 40 healthy nomal subjects, including 10 monozygotic (MZ) and 10 dizygotic (DZ) twin pais, ascetained fom a twin cohot composed of all same-sex twins bon in Finland between 1940 and 1957 [Kapio et al., 1990]. These maps evealed a nonunifom genetic continuum, in which bain stuctue was inceasingly simila in subjects with inceasing genetic affinity, moe so in heteomodal association aeas than in othe egions. Genetic factos significantly influenced cotical stuctue in Boca s and Wenicke s language aeas, as well as fontal bain egions ( MZ > 0.8). Peliminay heitability estimates indicated that localized middle fontal cotical egions, nea Bodmann aeas 9 and 46, displayed a 90 95% genetic detemination of stuctue. The emakably high coelations obseved between MZ twin pais indicate that MZ cotwins ae vitually identical in tems of gay matte concentation in these egions. Peliminay coelations wee pefomed, suggesting that fontal gay matte diffeences may be linked to Speaman s g, which measues successful test pefomance acoss multiple cognitive domains. The findings wee subsequently eplicated in independent volumetic studies [Baae et al., 2001; Wight et al., 2002], which examined heitabilities of Bodmann aea volumes using vaiance components analysis. Heitability of Bain Stuctue in Twins Discodant fo Schizophenia Stuctual o functional bain abnomalities that ae expessed in individuals with schizophenia and some of thei unaffected elatives ae likely to eflect genetic pocesses that confe vulneability to the disode. In contast, abnomalities that ae obseved in individuals with schizophenia but not thei elatives could eflect nonshaed (genetic o individual-specific envionmental) causative factos, and pocesses seconday to the effects of long-tem psychotic illness o its teatment [Cannon et al., 1998]. The potential fo neuoimaging methods to detect makes of genetic susceptibility to schizophenia was fist evidenced in sibling studies, in which ou goup and othes documented diffeences in egional cotical bain volumes and venticula volume in the unaffected fistdegee elatives of patients with schizophenia [Cannon et al., 1998; Staal et al., 2000]. While these studies may demonstate genetic influences on vaious neuoanatomic featues, the discodant twin design povides a unique oppotunity to evaluate vaious cotical featues fo a dosedependent elationship with genetic liability to schizophenia. This is done by compaing the unaffected MZ cotwins of patients with schizophenia, who ae genetically identical to the affected poband, the unaffected DZ cotwins of pobands, who shae on aveage half thei genes with the affected individual, and nomal contol subjects, who epesent the base ate of schizophenia-associated genes in the geneal population. The symptoms of schizophenia (e.g., pofound social and motivational deficits, fomal thought disode, and infomation-pocessing deficits) imply disuption to the most ecently evolved bain systems that suppot highe-ode cognitive activity. To investigate the topogaphy of genetically encoded deficits in cotical gay matte in schizophenia, we ceated the fist thee-dimensional cotical suface maps of intapai diffeences in MZ and DZ twins discodant fo SZ (10 discodant pais of each zygosity), along with 10 pais of demogaphically matched contol twins of each zygosity [Cannon et al., 2002] (Fig. 3). Within each pai of discodant MZ twins, a thee-dimensional map of gay matte volume in the schizophenic patient was subtacted fom that of his o he MZ cotwin, afte both images wee elastically ealigned to standad steeotaxic space using the cotical patten matching pocedues descibed above. This pocedue matches locations with the same elation to the pimay folding patten acoss subjects. The within-pai diffeence images wee then aveaged acoss pais, isolating the nongenetic, disease-specific vaiation in gay matte volume by eliminating genetic souces of vaiability between cases and contols. This map detected gay matte eductions of 5 8% in dosolateal pefontal cotex (BA 9/46), Boca s aea (BA 44/45), pemoto cotex and fontal eye fields (BA 6/8), supeio paietal lobule (BA 7/40), Heschl s gyus (BA 41/ 42), and middle tempoal gyus (BA 21) (Fig. 3a). The obseved disease-elated deficits in gay matte do not appea to eflect seconday phenomena, as they wee associated with inceased seveity of negative and positive symptoms and with cognitive dysfunction, but not with duation of illness o antipsychotic dug teatment. Additionally, a map encoding gay matte vaiation associated with genetic poximity to a patient (MZ cotwins > DZ cotwins > contol twins) isolated deficits pimaily in pola and dosolateal pefontal cotex, indicating substantial genetic influence on these cotical egions (Fig. 3b). In each 521

4 Figue 2. Figue 3.

5 Genotype-Phenotype Mapping in Schizophenia case, statistical significance was confimed though analysis of 10,000 Monte Calo pemutations, and the emaining cotex was shown to be significantly less affected by contast analysis. Genetic and disease-specific influences thus appea to affect gay matte in patially nonovelapping aeas of pedominantly heteomodal association cotex, changes that may act synegistically in poducing ovet behavioal featues of the disode. Ou stuctual findings ae futhe bolsteed by functional neuoimaging wok assessing woking memoy-elated cotical physiology duing pefomance on a woking memoy task in the nonpsychotic siblings of patients with schizophenia [Callicott et al., 2003]. These investigatos found that despite intact pefomance on the task siblings of schizophenia patients had an exaggeated physiological esponse in the ight dosolateal pefontal cotex, qualitatively simila to that obseved in pio fmri studies of patients with schizophenia. This exaggeated esponse implies inefficient pefontal infomation-pocessing in individuals with a high genetic load fo schizophenia. Collectively, these data suggest that isk fo schizophenia is inceased by the inheitance of alleles that contibute to gay matte deficits and disuption of pefontal cotical cicuity. We have extended this computational bain-mapping appoach to some medial and midline bain stuctues implicated in schizophenia, to examine genetic vesus shaed o disease-specific envionmental contibutions to callosal anatomy and hippocampal volume [Na et al., 2002b; van Ep et al., 2004]. Specifically, in a patially ovelapping sample of twin pais discodant fo schizophenia and healthy contol twins (N ¼ 40 pais; 10 MZ and 10 DZ twin pais discodant fo schizophenia, and 10 contol pais of each zygosity), we used anatomical mesh modeling methods to deive goup aveage and suface vaiability maps of the callosum. As the majo intehemispheic commissue of the bain, the copus callosum is impotant fo intehemispheic tansfe of infomation. Although seveal othe studies have documented abnomalities of the copus callosum in patients with schizophenia (e.g. DeQuado et al., 1996; Keshavan et al., 2002], the only othe study to examine callosal integity in the non-ill MZ cotwins of patients with schizophenia [Casanova et al., 1990a,b] found an upwad bowing of the callosum in the affected, elative to the unaffected, cotwin. Consistent with these findings, we obseved vetical displacements of the callosum in patients with schizophenia, which wee most ponounced in males. Howeve, diffeences in the degee of vetical displacement wee obseved between dizygotic, but not monozygotic cotwins discodant fo schizophenia. Like thei affected cotwins, the unaffected monozygotic cotwins of the schizophenia pobands exhibited significant callosal displacements, suggesting that genetic athe than disease-elated o shaed envionmental influences contibute to alteed callosal mophology in schizophenia [Na et al., 2002a] (Fig. 3c). Lateal and thid venticle enlagements wee associated with callosal displacements. An upwad bowing of the callosum may thus povide an easily identifiable neuoanatomic make that may identify individuals possessing a biological vulneability fo schizophenia. In a sepaate investigation on a sample of 16 MZ and 32 DZ twin pais discodant fo schizophenia, 7 MZ pais concodant fo schizophenia, and matched goups of healthy twins (28 MZ and 26 DZ pais), we used mixedmodel egession, coelational, and vaiance components (a) Depicts the degee of similaity (expessed in tems of % diffeence) of the distibution of gay matte density (GMD) in monozygotic (MZ) and dizygotic (DZ) twins. MZ twins ae almost pefectly coelated in GMD measues, paticulaly in fontal (F), sensoimoto (S/M), and peisylvian language cotices, suggesting stong genetic contol of bain stuctue in these egions, but not othes (shown in blue). Fatenal twins ae significantly less alike in fontal cotices, but ae % coelated in peisylvian language-elated cotex and spatial association cotices, including supamaginal and angula gyi. Colo-coded Figue 2. maps show the pecentage eduction in intapai vaiance fo each cotical egion. (b) The significance of genetic contol of gay matte distibution. Bain egions fo which cotical gay matte distibution is unde significant genetic contol ae shown in ed. Fontal (F) and lateal tempoal (T) egions show significant heitability, consistent with thei nea-identity in identical twins (a) and the weake coelations obseved in fatenal twins, who ae less simila genetically. Wenicke s aea shows significantly highe heitability in the left hemisphee (W left ), which is geneally dominant fo language function [Thompson et al. 2001]. (a) In discodant twins, disease-specific cotical gay matte deficits wee found in dosolateal pefontal cotex (PF), supeio tempoal gyus (STG), and supeio paietal lobule (P). Diseasespecific deficits coelated with symptom seveity and woking and episodic memoy impaiment, but not with illness duation o teatment. (b) Significance map of genetic liability-elated deficits: Gay matte deficits coelated with genetic poximity to a patient in pola and supeio pefontal cotex [Cannon et al. 2002]. (c) Callosal suface aveages mapped in goups defined by Figue 3. biological isk fo schizophenia. Aveage anatomical mesh models of the copus callosum ae shown in diffeent colos to illustate goup diffeences. Midsagittal callosal aveages ae mapped in the following: (1) schizophenia patients and nomal contols; (2) unaffected MZ cotwins of the schizophenia pobands and MZ contol twin pais, indicating genetic factos contibute to callosal displacement in schizophenia, and (3) unaffected DZ cotwins of the schizophenia pobands vesus thei cotwin with SZ. 523

6 Beaden et al. Figue 4. Least squaes mean hippocampal volumes acoss isk goups. CC indicates concodant; MZ, monozygotic; DC, discodant; DZ, dizygotic. Eo bas epesent SEM. analyses to examine the elative contibutions of genetic and envionmental factos to hippocampal volume eduction in schizophenia. Pobands hippocampal volumes wee smalle than those of thei non-sz MZ and DZ cotwins and healthy subjects, and pobands nonill cotwins hippocampal volumes wee smalle than those of healthy subjects, but nonill MZ and DZ cotwins of SZ patients did not diffe fom each othe (Fig. 4). The intaclass coelations (ICCs) fo hippocampal volumes among healthy MZ pais wee lage than those found in healthy DZ pais, but the ICCs fo hippocampal volumes among discodant MZ and DZ pais wee equivalent. Results fom vaiance components analysis futhe indicated that the effect of additive genes on hippocampal volume (coected fo cotical gay matte volume) is 71% in the healthy twins, but only 42% in the discodant twins. Togethe, these findings indicate that while hippocampal volume in healthy subjects is unde substantial genetic contol, hippocampal volume in SZ patients and thei elatives appeas to be influenced to a geate extent by unique and shaed envionmental factos [van Ep et al., 2004]. A simila patten of esults was obseved in a Dutch twin sample [van Haen et al., 2004]. These esults extend those of pio studies demonstating medial tempoal abnomalities in the unaffected elatives of schizophenia patients [Seidman et al., 2003; Tepest et al., 2003]. Futhemoe, these findings convege well with the patten of neuocognitive deficits associated with genetic isk fo schizophenia, whee unaffected elatives (who pesumably cay susceptibility genes fo the illness) show a pofile of memoy impaiment intemediate between nomal contols and thei ill elatives (fo whom disease-specific factos may contibute to geate seveity of deficit; see Tandafi et al. [2006] fo a meta-analysis). Although hee we did not examine specific candidate genes that may contibute to the obseved hippocampal alteations, bain-deived neuotophic facto (BDNF) is widely expessed in the hippocampus and has been implicated in the neuobiology of schizophenia. Szeszko et al. [2005] found diffeences in hippocampal volume as a function of BDNF (val66met) genotype in a combined sample of schizophenia patients and contols and, secondly, that genotype explained moe vaiance in hippocampal volume fo schizophenia patients elative to healthy voluntees. This suggests that the BDNF gene may contibute to vaiation in human hippocampal volume, and that this effect may be amplified in patients with schizophenia. Linkage and Association Analyses of the DISC1 Locus, Woking Memoy, and Pefontal Cotical Volume Given that abnomalities of woking memoy and pefontal cotical stuctue and function ae associated with genetic liability to schizophenia, it should be possible to identify specific genes that undelie these distubances. Fo example, Weinbege and colleagues have epoted evidence of one such genetic influence the met/val polymophism of the COMT (catechol-o-methyltansfease) gene on chomosome 22q, with val alleles pomoting moe apid beakdown of synaptic dopamine leading to pefontal hypofunction duing pefomance on a woking memoy task in patients with schizophenia [Egan et al., 2001]. These findings have now been extended to show a significant effect of COMT genotype on woking memoy pefomance (assayed by the n-back task) fo patients with schizophenia, thei healthy siblings, and contols [Goldbeg et al., 2003], as well as diffeential esponse to amphetamine as a function of COMT genotype, suppoting the notion of a chaacteistic inveted- U functional-esponse cuve to inceasing pefontal dopamine signaling [Mattay et al., 2003]. In addition, the G-potein signaling subtype 4 (RGS4) gene, which is located on chomosome 1q21, a egion that has been linked with schizophenia in a numbe of studies [Haison and Owen, 2003], was ecently shown to be associated with educed pefontal cotical gay matte volume in neuoleptic-naïve fist-episode schizophenia patients, 524

7 Genotype-Phenotype Mapping in Schizophenia but not in contols [Pasad et al., 2005]. Futhemoe, in a sample of child-onset schizophenia patients, Addington et al. [2006] ecently found that a isk allele at the neuegulin locus was associated with pooe pemobid social functioning, as well as a diffeent tajectoy of gay and white matte volume change ove time, suggesting the intiguing possibility of a disease-specific patten of gene action in schizophenia. Anothe potential susceptibility locus that has shown eplicated evidence of linkage with schizophenia and may affect pefontal cotical function is the disupted-in-schizophenia 1 (DISC1) gene on chomosome 1q42.1. In a lage Scottish pedigee, a balanced tanslocation in this egion (1q42.1;11q14.3) was stongly linked to psychopathology, including schizophenia, mania, and depession [Milla et al., 2000; St Clai et al., 1990]. In addition, the peak linkage signal obseved in the 1q42 egion within the Finnish population was intagenic to DISC1 [Ekelund et al., 2001, in pess; Hennah et al., 2003], and seveal othe linkage findings have also pointed to this egion [Cutis et al., 2003; Ekelund et al., 2000; Hwu et al., 2003]. DISC1 is tanslated to a potein that impacts on neuodevelopmental and neuochemical pocesses that ae likely to be involved in the pathophysiology of SZ, including neuite outgowth, synaptogenesis, and glutamategic tansmission [Milla et al., 2003; Miyoshi et al., 2003; Mois et al., 2003]. The egional expession of DISC1 in bain tissue appeas to be geatest in the hippocampus [Ma et al., 2002]. Recently, thee haplotypes incopoating diffeent blocks of single nucleotide polymophic (SNP) makes in the DISC1 and immediately adjacent TRAX genes wee found to be associated with SZ (two unde- and the othe ove-tansmitted to affected cases) in a study of multiplex families fom Finland [Hennah et al., 2003]. Moeove, DISC1 is nea the peak linkage signal obseved in a genome scan in seveal lage Scottish families multiply affected with bipola disode [Macgego et al., 2004], suggesting that DISC1 may confe genealized susceptibility to a boade psychopathological phenotype [Poteous et al., 2006]. Seveal ecent findings suggest that the DISC1 locus contibutes to alteations in pefontal cotical and hippocampal stuctue and function, and alteed woking and declaative memoy pefomance in schizophenia patients and thei elatives. Fist, using a combined linkage and association analysis stategy in dizygotic Finnish twins discodant fo schizophenia [Gaspeoni et al., 2003] found that allelic vaiation in a make located nea DISC1 was associated with vaiation in spatial woking memoy pefomance. Othe linkage studies in the Finnish population have epoted associations of haplotypes within the DISC1 gene with visual woking memoy [Hennah et al., 2005], and vebal leaning and memoy (semantic clusteing) [Paunio et al., 2004]. Moeove, Callicott et al. [2005] found that a common SNP within the DISC1 gene (Se704Cys) was associated with schizophenia in a family-based sample, and that allelic vaiation at this locus was associated with alteed hippocampal stuctue and function in healthy subjects. Recently, we applied the bain mapping algoithms descibed above to genetic linkage and association tests of DISC1 and anothe putative schizophenia susceptibility gene on chomosome 1q42, tanslin-associated facto X (TRAX). We examined a seies of haplotype blocks of single-nucleotide polymophic makes (SNPs) fom a segment of 1q42 spanning the DISC1 and TRAX genes fo association with schizophenia, and seveal endophenotypic taits thought to be associated with disease pathogenesis. In the samples of Finnish twin pais concodant and discodant fo SZ and healthy contol twins descibed above, we found that a common haplotype incopoating thee SNP makes nea the tanslocation beak point of DISC1 (odds atio, 2.6 [P ¼ 0.02]) and a ae haplotype incopoating fou makes fom the DISC1 and TRAX genes (odds atio, 13.0 [P ¼ 0.001]) wee significantly oveepesented among individuals with schizophenia [Cannon et al., 2005]. These haplotypes wee also associated with seveal quantitative endophenotypic taits peviously obseved to covay with schizophenia and genetic liability to schizophenia; specifically, impaiments in shot- and long-tem memoy functioning and educed gay matte density in the pefontal cotex (Fig. 5). In addition, while the ae HEP2/HEP3 haplotype was not associated with hippocampal volume, thee was a tend towad association of the homozygous HEP1 haplotype with educed hippocampal volume. Thus, allelic vaiation within the DISC1 and TRAX genes on chomosome 1q42 may contibute to genetic isk fo schizophenia though disuptive effects on the stuctue and function of the pefontal cotex, medial tempoal lobe, and othe bain egions. These effects ae consistent with the known function of these genes in tems of thei poduction of poteins that play oles in neuitic outgowth, neuonal migation, synaptogenesis, and glutamategic neuotansmission. Howeve, it is impotant to note that the haplotypes examined hee did not contain the Se704Cys SNP identified by Callicott et al. The lack of convegence of these findings suggests that othe isk alleles may be in linkage disequilibium (LD) with the Se704Cys polymophism, and that the inceased isk may be due to the ovetansmission of a DISC1 haplotype that does not include this paticula allele. Diffeences in esults may also be a function of SNP make density used acoss studies. Bolsteing this conclusion, a pio case contol association study of patients with schizophenia and bipola disode using fou common SNPs and a micosatellite in the DISC1 egion [Devon et al., 2001] found neithe cosegegation with disease status no significant association; howeve, they did not detect LD between all the makes in the contol population, suggesting that an even geate density of infomative makes is equied to test igoously fo association in this genomic egion. In summay, these twin studies confim pio evidence of genetic influences on gay matte density in fontal bain egions. They also povide conveging evidence fo a ole of chomosome 1q42 in the pathogenesis of schizophenia, by 525

8 Beaden et al. demonstating linkage and association of makes of the TRAX and DISC1 genes with pefontal cotical gay matte deficits in twins discodant fo schizophenia. Taken togethe, these findings povide compelling evidence that specific genetic loci suspected to pedispose to schizophenia may affect quantitative vaiation in neual indicatos undelying disease pathogenesis. Hee, we have illustated these appoaches using samples of healthy monozygotic (MZ) and dizygotic (DZ) twin pais, as well as MZ and DZ twin pais discodant fo schizophenia, but the methods can be genealized to othe classes of elatives and to othe diseases as well. Bain Mapping in Rae Neuogenetic Disodes Associated with Schizophenia Figue 5. Statistical anatomical maps of DISC1/TRAX Associations with cotical gay matte density (GMD): (a) Aeas of the cotical suface in which significant eductions in GMD ae associated with a common haplotype (HEP1; TCG) of a 3-SNP block of makes located nea the tanslocation beakpoint on the DISC1 gene; (b) GMD eductions associated with a ae haplotype (AATG) of a 4-SNP block of makes spanning the DISC1 and TRAX genes. Top, left, and ight views of each map ae displayed [Cannon et al. 2005]. A complementay appoach in the seach fo susceptibility genes fo schizophenia involves the study of chomosomal abnomalities such as tanslocations, duplications, and deletions, which might segegate with the disode. Reseach effots on othe complex diseases fo example, the stong association between ealy-onset dementia and Down s syndome suggest that this stategy may be paticulaly valuable fo undestanding the genetics and undelying pathophysiology of diseases with complex inheitance pattens [Muphy, 2002]. The 22q11.2 Deletion Syndome (Velocadiofacial/ DiGeoge Syndome) involves cadiac and caniofacial anomalies, maked deficits in visuospatial cognition, and elevated ates of psychopathology. In most diagnosed cases, the syndome esults fom a 3 megabase (Mb) de novo deletion at chomosome 22q11.2. This egion of the genome is thought to be paticulaly susceptible to chomosomal eaangement due to the goups of low copy Figue 6.

9 Genotype-Phenotype Mapping in Schizophenia epeat sequences flanking the deletion beakpoints, which may cause misalignment due to high sequence homology [Shaffe and Lupski, 2000]. Twenty-five to 30% of adults with this syndome develop schizophenia, making 22q11.2DS one of the geatest known isk factos fo schizophenia identified to date [Muphy et al., 1999]. The geatly inceased isk fo psychosis in this syndome suggests that a gene o genes within the 22q11.2 deletion egion may contibute to schizophenia susceptibility in the boade population. Suppot fo this notion is povided by genetic linkage and association studies implicating genes within the 22q egion in schizophenia (i.e., poline dehydogenase (PRODH), COMT, ZDHHC8, and G-potein-coupled ecepto kinase (GRK3; Gogos et al., 1999; Mukai et al., 2004; Patelini et al., 2005], documentation of 22q11 as a egion of inteest in the meta-analysis of Lewis et al. [2003], and the finding that mice heteozygously deleted fo some of the genes in this egion have sensoimoto gating and memoy impaiments simila to those obseved in schizophenia [Gogos et al., 1998, 1999; Paylo et al., 2001]. As such, individuals with this syndome may have genetically detemined diffeences in bain anatomy that pedispose to schizophenia [van Amelsvoot et al., 2004], although cuently the mechanism fo the development of schizophenia in individuals with this syndome is not known. Using the cotical patten matching methods descibed above, we mapped cotical thickness in millimetes based on stuctual MRI images of 21 childen with confimed 22q11.2 deletions and 13 demogaphically matched healthy compaison subjects [Beaden et al., 2006]. All paticipants with 22q11.2DS had the same 3 Mb typical deletion. Thickness was mapped at 65,536 homologous points, based on the 3D distance fom the cotical gay white matte inteface to the extenal gay-csf bounday [Thompson et al., 2005]. A patten of egionally specific cotical thinning was obseved in supeio paietal cotices and the ight paietooccipital cotex, egions citical fo visuospatial pocessing, and bilateally in the most infeio potion of the infeio fontal gyus (pas obitalis), a key aea fo language development (Fig. 6]. Even in this modest sample size, the obseved gay matte deficits appea to have functional implications, as gay matte volume was significantly coelated with IQ in the childen with 22q11.2DS, although this elationship was not significant in the contol sample (Fig. 7). Seveal of the 30 genes encoded in the deleted segment ae highly expessed in the developing bain, and known to affect ealy neuonal migation. These quantitative maps of cotical integity thus eveal how haploinsufficiency fo genes in the 22q11.2 egion can affect cotical development, and suggest a possible undelying pathophysiology of the neuobehavioal phenotype. Notably, the chaacteistic 22q11.2DS cognitive pofile involving elative stengths in vebal memoy, in contast to maked deficits in visuospatial memoy beas stiking similaity to that seen in anothe genetic deletion syndome, Williams Syndome [Beaden et al., 2002]. Howeve, unlike Williams Syndome (WS), patients with 22q11.2DS ae not geneally epoted to be hypesociable, o to show paticula stengths in musical ability [Kamiloff-Smith et al., 2004]. Using identical cotical thickness mapping methods to those descibed hee, Thompson et al. [2005] obseved a failue of cotical matuation in patients with WS, involving a zone of ight hemisphee peisylvian cotex that was 5 10% thicke in WS than in matched contols, despite pevasive gay and white matte deficits, but with coesponding deficits in the adjacent dosal steam, including supeio paietal bain egions. Recently developed image analysis methods have evealed inceased gyification bilateally in occipital egions and ove the cuneus in WS subjects [Gase et al., 2006; Tosun et al., 2006], as well as numeous cotical folding abnomalities in bain egions associated with multiple sensoy modalities, as well as cognitive and emotional behavio [Van Essen et al., 2006]. Using functional bain imaging duing visual pocessing tasks, Meye-Lindenbeg et al. [2004] identified a patten of hypoactivation in subjects with WS in the paietal potion of the dosal steam, concomitant with gay matte volume (a) Statistical significance maps of cotical thickness eductions in 22q11.2DS, as compaed to typically developing contol childen, plotted as a map of P-values. A pevious finding by Eliez et al. [2000] indicating educed paietal lobule volume in 22q11.2DS, even afte adjusting fo diffeences in bain volume, is consistent with the thinning of paietal cotex seen hee. (b) Asymmety effects in 22q11.2 vesus Contols: Maps of cotical thickness asymmety expessed as a pecentage, fo contol subjects (top left panel) and 22q11.2DS (top ight panel). Negative values on the colo ba (puple and magenta) encode a geate thickness in the LH (i.e., leftwad asymmety), while positive values (oange and ed) epesent geate thickness in the RH (i.e., ightwad asymmety). Bottom panel depicts maps of significant cotical thickness asymmety, in contols (bottom left) and 22q11.2DS (bottom ight). Blue-shaded egions ae not significantly diffeent Figue 6. between LH and RH. Measues of asymmety ae shown on one hemisphee only as they ae, by definition, the same fo both hemisphees. Rightwad (R > L) asymmeties of cotical thickness wee of geatest magnitude in the infeio fontal gyus in both 22q11.2DS and contol childen but wee moe extensive in the bains of 22q11.2DS paticipants. (c) Developmental Effects: Bain egions in which age is significantly negatively coelated with cotical thickness, shown sepaately fo typically developing contols (top) and age-matched subjects with 22q11.2DS (bottom). Consistent with independent studies of cotical development and aging [Gogtay et al., 2004; Sowell et al., 2003], contols showed localized egions of cotical thinning in supeio paietal and middle tempoal egions associated with inceasing age, but childen with 22q11.2DS showed moe widespead aeas of age-elated cotical thinning, paticulaly in the infeio tempoal gyus and paietal egions. 527

10 Beaden et al. Figue 7. Scatteplot of cognitive outcome vaiables with gay matte volume: Fo childen with 22q11.2DS, but not typically developing contols, gay matte volume was a significant pedicto of Full Scale IQ (FSIQ). eduction in the immediately adjacent paieto-occipital/ intapaietal sulcus. Using path analysis, they found suppot fo thei hypothesis that the stuctual abnomalities in the paietal egion may seve as a oadblock to dosal steam infomation flow in WS. Similaly, the localized thickness deficits in 22q11.2DS may undelie the visuospatial cognitive impaiments chaacteistic of the syndome, by affecting the flow of infomation though distibuted neual systems; this hypothesis awaits futhe testing using multimodal imaging appoaches, as illustated by the pioneeing wok of Meye-Lindenbeg et al. [2006]. Inteestingly, the cotical anomalies obseved in this goup of childen and adolescents with 22q11.2 deletions do not closely esemble those seen in schizophenia, whee pefontal and tempoal egions show the geatest gay matte deficits [Wight et al., 2000]. Developmental factos ae likely to play an impotant ole in these diffeences. As seen in Figue 6c, we obseved a modeate invese elationship between age and cotical thickness in ou coss-sectional study, in both patients with 22q11.2DS and healthy contols, although qualitative inspection of the maps suggests that thee may be a moe ponounced effect of age on cotical thickness in 22q11.2DS as compaed to typically developing contols. Contols showed localized egions of cotical thinning in supeio paietal and middle tempoal egions associated with inceasing age, consistent with independent studies of cotical development and aging [Gogtay et al., 2004; Sowell et al., 2003], but childen with 22q11.2DS showed moe widespead aeas of cotical thinning that wee significantly coelated with age, paticulaly in the infeio tempoal gyus bilateally, and in paietal egions. In addition, using identical cotical patten matching methods to those descibed hee, Thompson et al. [2001] and Vidal et al. [2006] mapped cotical changes ove time in adolescents with childhood onset of schizophenia. This study evealed that ealy deficits in paietal bain egions pogessed anteioly into tempoal lobes, engulfing sensoimoto and dosolateal pefontal cotices ove a 5-yea peiod. This tajectoy appeas to be an exaggeation of the nomal sequence of denditic puning and myelination [Gogtay et al., 2004]. Only the latest changes included dosolateal pefontal cotex and supeio tempoal gyi, deficit egions found consistently in adult studies, suggesting that these stuctual changes occu late in the couse of illness. Moe ecent wok has shown that the dynamic tajectoy of deficits is diffeent in childen with ealy-onset bipola illness [Gogtay et al., 2007], and may be opposed by cetain types of psychotopic agents (e.g., atypical antipsychotics o mood stabilizes; [Beaden et al., in pess; Time-lapse mapping eveals diffeent disease tajectoies in schizophenia depending on antipsychotic teatment, submitted]). In this study, involving childen and adolescents with the 22q11.2 micodeletion, we did not find evidence fo diffeences in pattens of cotical thickness between patients with and without psychiatic disodes. Howeve, using quantitative measues, we peviously found a elationship between educed tempoal gay matte and elevated Thought Poblems, as assessed by the Child Behavio Checklist [Beaden et al., 2004]. Consistent with this, Campbell et al. (2006) ecently obseved a significant positive coelation between seveity of schizotypy scoe and gay matte volume in tempoo-occipital egions and basal ganglia. Emotional and social poblems wee associated with gay matte volume in fontostiatal egions, suggesting that quantitative indices of psychopathology may be elated to diffeences in bain development in this syndome, even in the absence of categoical syndome-based goup diffeences. In the only longitudinal neuoimaging study of 22q11.2DS to date, Gothelf et al. [2005] found that the COMT low-activity (Met) allele was associated with decline in pefontal cotical volume and cognition, and with development of psychotic symptoms duing adolescence. These intiguing findings highlight the impotance of investigating the evolution of psychotic symptoms in elation to genes and neuoanatomy ove time in this syndome. CONCLUSIONS AND FUTURE DIRECTIONS The endophenotype appoach is a sensitive method fo measuing phenotypic vaiation that may make it easie to identify susceptibility genes and thei mechanisms of action fo taits with complex inheitance pattens. Such investigations may be futhe empoweed by complementay stategies involving chomosomal abnomalities associated with schizophenia, which offe an altenative appoach to help localize causative genes and bette undestand the genetic complexity of the illness [Bassett 528

11 Genotype-Phenotype Mapping in Schizophenia et al., 2000]. With egad to this stategy, it should be noted that it is not assumed that cytogenetic eaangements such as the 22q11.2 micodeletion account fo a substantial popotion of the tait vaiance o disease liability in schizophenia oveall [Poteous et al., 2006]. Rathe, the study of such cytogenetic anomalies may povide anothe window into discoveing a potential genetic oute of causation. As such, the examination of quantitative endophenotypes in these ae disodes and thei potential ovelap with CNS indicatos in schizophenia may offe a complementay stategy to examine genotype phenotype elationships, in which genotype is clealy identified. To deciphe the complex natue of genotype phenotype elationships within the multiple neual systems compomised in neuopsychiatic syndomes such as schizophenia, sophisticated computational bain mapping methodologies ae needed. As illustated hee, these methods allow us to epesent population vaiability in neual taits, and to pobe thei heitable and molecula genetic bases. Moeove, the high heitability estimates obtained fo a vaiety of neuoanatomic taits suggest that neuoimaging paadigms may povide moe eliable measues than behavioal and clinical assays, esulting in impoved sensitivity to genetic vaiation. These findings illustate the way in which imaging-genetics paadigms can advance ou undestanding of the contibution of specific genetic vaiants to the neuobehavioal phenotype of schizophenia. The methods eviewed hee fo hypothesis diven, voxelbased association analyses fo candidate genes that may pedispose to schizophenia can also be applied in genomewide linkage and association studies. Clealy, pocedues to contol fo multiple-testing must be futhe efined in such applications, as the pemutation methods developed to handle these issues thus fa would not be computationally efficient unde those cicumstances. Howeve, as it is not feasible to conduct neuoimaging studies on thousands of subjects in the nea futue, as would be equied fo this type of investigation, it is moe likely that this methodology will fist be applied to focal linkage and association analyses of specific genomic egions that have been peviously implicated in the pathogenesis of a paticula disode. Futue studies ae waanted to elucidate how multiple genes inteact in detemining dysfunction in vaious neuobehavioal domains in schizophenia, and to claify how much these gene endophenotype elationships ovelap with othe seious psychiatic disodes with complex inheitance pattens, paticulaly bipola disode. Ou cuent investigations to addess these questions include a populationbased study of twins discodant fo schizophenia and bipola disode, and studies of extended pedigees multiply affected with sevee bipola disode in genetically isolated populations, applying the above-mentioned methodologies. 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