General Summary I Alvarado, F Sissingh and J Licinio

UCLA, Los Angeles, CA, USA

Molecular Psychiatry (2002) 7, 665–668. doi:10.1038/ teins of epidermal growth factor (EGF) and its homol- sj.mp.4001225 ogues are known to regulate development of the dopaminergic neurons as well as dopamine metabolism, and might be involved in schizophrenic pathology and/or etiology. To test this possibility, levels of these SCIENTIFIC CORRESPONDENCE proteins and their receptors were determined in post- Association of a polymorphism in the promoter mortem brains of schizophrenic patients and control region of the serotonin 5-HT2C receptor gene with subjects in the present study. Among members of the tardive dyskinesia in patients with schizophrenia EGF family examined, EGF were specifically decreased ZJ Zhang, XB Zhang, WW Sha, XB Zhang, in the prefrontal cortex and striatum, where the dopa- GP Reynolds minergic neurons innervate. Conversely, receptor levels for EGF were increased in the same region. More- Tardive dyskinesia (TD) is a major side effect of over, the reduction in EGF was also seen in serum of chronic treatment with antipsychotic drugs. As the 5- schizophrenic patients, even in drug-naive patients. HT2C receptor is involved in motor function including However, chronic administration of haloperidol to rats production of dyskinesias, the authors have investi- had no effect on EGF levels. These findings suggest a gated whether functional polymorphisms of the pro- strong link between abnormal EGF receptor signaling moter region of the 5-HT2C receptor gene may be asso- and schizophrenia that might underlie the domami- ciated with TD. They studied 42 schizophrenic nergic dysfunction in this illness. patients with persistent TD, and 50 matched patients without dyskinesias, and identified a significant excess of one allelic variant in the TD group. As haplotypes Decreased phorbol ester binding in the containing this allele have higher promoter activity, parahippocampal gyrus from subjects with the authors conclude that genetic control of 5-HT2C schizophrenia is not associated with changes in receptor expression may contribute to susceptibility to protein kinase C drug-induced dyskinesias. E Scarr, G Pavey, PI Robinson, K Opeskin, DL Copolov, B Dean No occurrence of the glutamate transporter EAAT2 The authors further investigated previous findings of A206G polymorphism in schizophrenic subjects decreased phorbol ester binding in the parahippocam- M Catalano, C Lorenzi, L Bocchio, G Racagni pal gyrus from subjects with schizophrenia. Phorbol esters bind to protein kinase C, which can be important A relative glutamatergic hypofunction is suspected to in responses to neurotransmitters. Changes in phorbol be involved in schizophrenia. Recent findings support- ester binding were confirmed but there were no ing this hypothesis, and the possible candidate role for changes in levels of protein kinase C isoforms or the gene encoding the glutamate transporter EAAT2, enzyme activity. This raises the possibility that other prompted the authors to study the A(G transition in phorbol ester binding sites are altered in schizo- codon 206 (Ser(Asn) of this gene in 124 schizophrenics phrenia. and 50 healthy controls of Italian descent. Negative finding seems to exclude any association between this polymorphism and schizophrenia, at least in this sam- Genome-wide multipoint linkage analyses of ple. multiplex schizophrenia pedigrees from the oceanic nation of Palau B Devlin, SA Bacanu, K Roeder, F Reimherr, ORIGINAL RESEARCH ARTICLES P Wender, B Galke, D Novasad, A Chu, K TCuenco, Abnormal expression of epidermal growth factor S Tiobek, C Otto, W Byerley and its receptor in the forebrain and serum of The oceanic nation of Palau has been geographically schizophrenic patients and culturally isolated over most of its 2000-year his- T Futamura, K Toyooka, S Iritani, K Niizato, tory. To localize genetic variants affecting liability to R Nakamura, K Tsuchiya, T Someya, A Kakita, schizophrenia, the authors scanned the genomes of five H Takahashi, H Nawa large Palauan pedigrees using over 400 genetic mark- Abnormality in dopaminergic function has often been ers. They found significant and suggestive linkage sig- implicated as a cause of schizophrenia. Diffusible pro- nals on chromosomes 5 and 3, respectively. Their General Summary 666 results suggest there are multiple genes conferring lia- Imbalance in dopamine neurotransmission and inter- bility to schizophrenia even in this small island popu- action between dopaminergic and serotonergic systems lation. has been suggested as a predisposing factor in the pathophysiology of ADHD. Using haplotype-based Relationship between adverse effects of haplotype relative risk (HHRR) and transmission dis-

antipsychotic treatment and dopamine D2 receptor equilibrium test (TDT) analyses, a significant preferen- polymorphisms in patients with schizophrenia tial transmission of the allele 861G of the serotonergic R Kaiser, PB Tremblay, F Klufmo¨ ller, I Roots, receptor 5-HTR1B in the total sample (for HHRR; c2 = J Brockmo¨ ller 7.4, P = 0.0065 and TDT; c2 = 6.4, P = 0.014) was observed. These preliminary data suggest an important Genetic variants in the dopamine D receptor (DRD2) 2 role for the serotonergic system in the development gene may modulate the severity of adverse effects of of ADHD. antipsychotics. In a prospective naturalistic study in 665 Caucasian schizophrenic patients, the authors × found no significant association between in tensity of Antiepileptic drugs and agents that inhibit voltage- acute dystonia, extrapyramidal symptoms, akathisia, gated sodium channels prevent NMDA antagonist and tardive dyskinesia and nine DRD2 polymorphisms. neurotoxicity Sequencing of the DRD2 coding region including exon– NB Farber, XP Jiang, C Heinkel, B Nemmers intron junctions revealed no new amino acid variants. Antagonists of the NMDA glutamate receptor produce Higher scores of self-reported schizotype in healthy a dishibitory state that causes excessive stimulation of young males carrying the COMT high activity allele cerebrocortical neurons, resulting in psychosis and D Avramopoulos, NC Stefanis, I Hantoumi, neurotoxicity. The authors report that several anticon- N Smyrnis, I Evdokimidis, CN Stefanis vulsants through different mechanisms can prevent the neurotoxicity associated with this NMDA receptor The authors tested the hypothesis that COMT genotype hypofunction (NRHypo) state. These agents might have for the functional Val158Met polymorphism might therapeutic benefits for conditions (eg Alzheimer’s dis- contribute to the variance of self-reported schizotypy ease, schizophrenia, bipolar disorder) in which an in the normal population. Results showed that self- NRHypo state may exist. reported schizotypy scores were significantly related to COMT genotype with individuals homozygous for the high activity allele showing the highest scores. This A genome-wide scan shows significant linkage adds to the list of evidence that COMT or a nearby gene between bipolar disorder and chromosome 12q24.3 in linkage disequilibrium is involved in the pathogen- and suggestive linkage to chromosomes 1p22–21, esis of schizophrenia. 4p16, 6q14–22, 10q26 and 16p13.3 H Ewald, T Flint, TA Kruse, O Mors A meta-analysis of the association between DRD4 The authors presented results of a genome scan on two polymorphism and Novelty Seeking families with bipolar disorder using 613 microsatellite AN Kluger, Z Siegfried, RP Ebstein markers. Significant linkage was found at D12S1639 An initial, exciting report about a correlation between with a parametric lod score of 3.42 (genome-wide P- DRD4 polymorphism and personality were followed by value 0.0417). Marker D1S216 yielded a parametric, inconsistent reports. To assess the evidence regarding affecteds-only lod score of 2.75 (genome-wide P-value the association between DRD4 polymorphism and Nov- 0.1622), which were supported by non-parametric elty Seeking, the authors combined, statistically, 20 multipoint analyses. Additional loci on chromosomes studies (n = 3907). This meta-analysis suggests that, on 4p, 6q, 10q and 16p yielded parametric lod scores average, there is no association between DRD4 poly- around or above 2. morphism and Novelty Seeking. However, a weak or complex association may exist—a possibility that requires further research. Novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene associated with bipolar affective Serotonergic system and attention deficit disorder hyperactivity disorder (ADHD): a potential M Nyegaard, AD Børglum, TG Bruun, DA Collier, susceptibility locus at the 5-HT1B receptor gene in C Russ, O Mors, H Ewald, TA Kruse 273 nuclear families from a multi-centre sample The SSTR5 gene is a candidate gene for bipolar affect- Z Hawi, M Dring, A Kirley, D Foley, L Kent, ive disorder (BPAD). SSTR5 forms functional heterodi- N Craddock, P Asherson, S Curran, A Gould, mers with DRD2, a major target of neuroleptic treat- S Richards, D Lawson, H Pay, D Turic, K Langley, ments in psychiatric disorders. The gene was M Owen, M O’Donovan, A Thapar, M Fitzgerald, sequenced in bipolar patients and 11 novel polymor- M Gill phisms were found. Significant association between Attention deficit hyperactivity disorder (ADHD) is a different SNPs in SSTR5 and bipolar disorder was highly heritable disorder affecting school-age children. found in a Danish and a British case-control sample

Molecular Psychiatry General Summary 667 yielding some support for involvement of this gene ⑀4). In this study, the authors found an increased fre- in BPAD. quency of the Glu318Gly mutation in familial AD in the Australian population. Neurotransmitter receptor-mediated activation of G- proteins in brains of suicide victims with mood A polymorphism of the brain-derived neurotrophic ␣ factor (BDNF) is associated with Alzheimer’s disease disorders: selective supersensitivity of 2A- ⑀ adrenoceptors in patients lacking the apolipoprotein E 4 allele J Gonza´ lez-Maeso, R Rodrı´guez-Puertas, JJ Meana, M Riemenschneider , S Schwarz , S Wagenpfeil, JA Garcıá-Sevilla, J Guimo´ n J Diehl, U Mu¨ ller, H Fo¨ rstl, A Kurz The authors analyzed a polymorphism of brain-derived The stimulation of [35S]GTP␥S binding by selective neurotrophic factor (BDNF) and discovered the BDNF agonists allows the functional evaluation of G-protein- C-270T polymorphism to be a relevant risk factor for coupled receptor abnormalities in postmortem brains. AD. In their sample of German patients, the T allele The sensitivities of ␣ -adrenoceptors, 5-HT sero- 2 1A frequency was higher in patients with AD; furthermore, tonin, ␮-opioid, GABA , and cholinergic muscarinic B the risk associated with the T allele was stronger in receptors were analysed in frontal cortexes of patients lacking the ApoE ⑀4 allele. They suggest that depressed suicide victims and matched controls. Only this potentially significant result be confirmed in a the ␣ -adrenoceptor-mediated stimulation of 2A larger sample of subjects. [35S]GTP␥S binding displayed a greater sensitivity whereas no changes were found in other receptor- mediated stimulations. The receptor-independent DRD4 promoter SNPs and gender effects on [35S]GTP␥S binding stimulation by mastoparan and the Extraversion in African Americans G-protein immunoreactivities were also similar in both EB Bookman, RE Taylor, L Adams-Campbell, ␣ RA Kittles groups. The finding demonstrates an 2A-adrenoceptor supersensitivity that is not related to increased amount Little is known about the relationship between the or enhanced intrinsic activity of G-proteins. dopamine D4 receptor gene and personality traits among African Americans. In this study, two DRD4 promoter polymorphisms were examined in African APOE-⑀4 and APOE −491A polymorphisms in Americans to determine if they contributed to variation individuals with subjective memory loss in personality. A strong association between the SM Laws, RM Clarnette, K Taddei, G Martins, −521C/T genotype and Extraversion among females A Paton, J Hallmayer, OP Almeida, DM Groth, was observed, providing further evidence that DRD4 SE Gandy, H Fo¨ rstl, RN Martins and gender differences contribute to variation in Nov- The identification of predictive or diagnostic genetic elty Seeking behaviors such as Extraversion. factors may improve accuracy of Alzheimer’s disease (AD) prediction or diagnosis, which currently can only The short DRD4 repeats confer risk to attention be made with a high degree of certainty in the deficit hyperactivity disorder in a family-based advanced stages of the disease. This study investigates design and impairs performance on a continuous the association between apolipoprotein E (APOE) geno- performance test (TOVA) type, −491A/T polymorphism, plasma apoE levels and I Manor, S Tyano, J Eisenberg, R Bachner-Melman, subjective memory loss. The authors report the ⑀4 M Kotler, RP Ebstein allele of APOE and the A allele of the −491A/T poly- The dopamine D4 receptor gene (DRD4) is the focus morphism to be significantly associated with ‘mem- of intense study regarding ADHD. In contrast to some ory complainers’. studies, preferential transmission of the short rather than the long (7-repeat) allele was observed in 178 tri- Association between presenilin-1 Glu318Gly ads from an Israeli population. Additionally, the mutation and familial Alzheimer’s disease in the authors tested subjects using a continuous performance Australian population test and increasing repeat size was accompanied by K Taddei, C Fisher, SM Laws, G Martins, A Paton, reduced number of errors of commission. There RM Clarnette, C Chung, WS Brooks, J Hallmayer, appears to be a complex relationship between DRD4 J Miklossy, N Relkin, PH St George-Hyslop, and ADHD. SE Gandy, RN Martins Mutations in the presenilin-1 (PS-1) gene are respon- Serotonin transporter gene promoter variants do not sible for many cases of early-onset, inherited Alzhei- explain the hyperserotoninemia in autistic children mer’s disease (AD). Of the 90 different mutations ident- AM Persico, T Pascucci, S Puglisi-Allegra, ified in the PS-1 gene, one mutation, Glu318Gly, has R Militerni, C Bravaccio, C Schneider, R Melmed, been found in cognitively normal individuals, in S Trillo, F Montecchi, M Palermo, D Rabinowitz, addition to AD patients, suggesting that it may act as KL Reichelt, M Conciatori, R Marino, F Keller a risk factor not unlike that of the major genetic risk The authors investigated contributions of 5-HT trans- factor for AD—the (4 allele of Apolipoprotein E (APOE- porter (5-HTT) gene promoter alleles to 5-HT blood lev-

Molecular Psychiatry General Summary 668 els in 132 autistic patients and 291 first-degree rela- nent and for the involvement of genes of the serotonin tives. 5-HTT gene promoter variants exert a small effect system. Based on previous results from the same group, on 5-HT blood levels in autistic children, which largely in the present study, the authors investigated further does not account for the hyperserotoninemia present the role of one of the genes of the serotonin system in many autistic patients. This effect, however, points (5HT1D() in conferring risk to OCD in a large sample toward a selection bias of hyper- or hypo-serotoni- of families. They confirmed their original finding of a nemic probands as possibly contributing to inconsist- preferential transmission of one of the variants of the encies among prior association studies. gene to the affected subjects from their parents. These results could have important implications for the role Absence of association between a polymorphic GGC of the 5HT1D␤ receptor gene in the pathogenesis and Ј repeat in the 5 untranslated region of the reelin treatment of OCD. gene and autism MO Krebs, C Betancur, S Leroy, MC Bourdel, C Gillberg, M Leboyer and the Paris Autism Research International Sibpair (PARIS) Study Depression: reduced number of granule cells in the hippocampus of female, but not male, rats due to Autism is a complex neurodevelopmental disorder prenatal restraint stress with genetic predisposition. The gene coding for reelin, C Schmitz, ME Rhodes, M Bludau, S Kaplan, P Ong, involved in neuronal migration, is located within a I Ueffing, J Vehoff, H Korr, CA Frye candidate region in autism (7q22). The TDT analysis Ј of the 5 UTR GGC polymorphism of the reelin gene The interrelations between prenatal stress and the found no evidence of linkage/association with autism development of depression in adulthood, preferentially in 167 families including 218 affected. Contradictory in females, are not understood. Here, the authors found to previous findings, these results challenge the role of a reduction of the number of hippocampal granule cells this reelin gene’s polymorphism in autism. due to a mild prenatal stress in female, but not in male, rats. These data are discussed as a first indication of 5HT1D␤ receptor gene implicated in the how mild prenatal stress can act as a gender-specific pathogenesis of obsessive-compulsive disorder: predisposing factor for developing neurobiological further evidence from a family-based association alterations reminiscent of those seen in human study depressives. E Mundo, MA Richter, G Zai, F Sam, J McBride, F Macciardi, JL Kennedy Obsessive-Compulsive Disorder (OCD) is a psychiatric J Licinio, MD condition with strong evidence for a genetic compo- Editor

Molecular Psychiatry