Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism

Original Article - click here for text.

Molecular Psychiatry advance online publication 24 November 2009; doi: 10.1038/mp.2009.118

R J Delahanty^1,8, J Q Kang^2,8, C W Brune³, E O Kistner⁴, E Courchesne⁵, N J Cox⁶, E H Cook Jr⁴, R L Macdonald² and J S Sutcliffe^1,7

1. ¹Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
2. ²Department of Neurology, Vanderbilt University, Nashville, TN, USA
3. ³Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago, Chicago, IL, USA
4. ⁴Department of Health Studies, The University of Chicago, Chicago, IL, USA
5. ⁵Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
6. ⁶Department of Medicine, The University of Chicago, Chicago, IL, USA
7. ⁷Department of Psychiatry, Vanderbilt University, Nashville, TN, USA

Correspondence: Dr JS Sutcliffe, Center for Molecular Neuroscience, Departments of Molecular Physiology and Biophysics and Psychiatry, Vanderbilt University, Nashville, TN 37232-8548, USA. E-mail:jim.sutcliffe@vanderbilt.edu

⁸These two authors contributed equally to this work.

Received 7 July 2009; Revised 10 September 2009; Accepted 22 September 2009; Published online 24 November 2009.

Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for 1–3% of cases. The 15q11-q13 region is subject to epigenetic regulation, and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABA_A receptor 3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. An analysis of wild-type and mutant 3 subunit-containing 132 or 332 GABA_A receptors shows reduced whole-cell current and decreased 3 subunit protein on the cell surface due to impaired intracellular 3 subunit processing. We thus provide the first evidence of an association between a specific GABA_A receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism relevant and the first maternal risk effect in the 15q11-q13 autism duplication region that is linked to a coding variant.

Researching Genetic Versus Nongenetic Determinants of Disease: A Comparison and Proposed Unification

SCIENCE TRANSLATIONAL MEDICINE 18 November 2009:
Vol. 1, Issue 7, p. 7ps8
DOI: 10.1126/scitranslmed.3000247

• Perspective - click here for article
  

1. John P. A. Ioannidis¹,²,³,*,
2. En Yun Loy⁴,
3. Richie Poulton⁵ and
4. Kee Seng Chia⁴,⁶,⁷

Author Affiliations

1. Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
2. Center for Genetic Epidemiology and Modeling, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, USA.
3. Biomedical Research Institute, Foundation for Research and Technology–Hellas, Ioannina, Greece.
4. Center for Molecular Epidemiology, National University of Singapore, Singapore.
5. Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
6. Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.

1. *Corresponding author. E-mail: jioannid@cc.uoi.gr

Abstract

Research standards deviate in genetic versus nongenetic epidemiology. Besides some immutable differences, such as the correlation pattern between variables, these divergent research standards can converge considerably. Current research designs that dissociate genetic and nongenetic measurements are reaching their limits. Studies are needed that massively measure genotypes, nongenetic exposures, and outcomes concurrently.

1H-MRS at 4 Tesla in minimally treated early schizophrenia

Original Article - To go to article, click here.

Molecular Psychiatry advance online publication 17 November 2009; doi: 10.1038/mp.2009.121

J R Bustillo^1,2, L M Rowland³, P Mullins⁴, R Jung^4,5,6, H Chen¹, C Qualls⁷, R Hammond¹, W M Brooks⁸ and J Lauriello¹

1. Department of Psychiatry, University of New Mexico, Albuquerque, NM, USA
2. Department of Neurosciences, University of New Mexico, Albuquerque, NM, USA
3. Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD, USA
4. The Mental Illness and Neuroscience Discovery Institute, Albuquerque, NM, USA
5. Department of Psychology, University of New Mexico, Albuquerque, NM, USA
6. Department of Neurology, University of New Mexico, Albuquerque, NM, USA
7. Department of Mathematics & Statistics, University of New Mexico, Albuquerque, NM, USA
8. Hoglund Brain Imaging Center, Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA

Correspondence: JR Bustillo, Department of Psychiatry, University of New Mexico, 1101 Yale st NE, MSC09 5030, Albuquerque, NM 87131-0001, USA. E-mail: jbustillo@salud.unm.edu

Received 11 February 2009; Revised 28 September 2009; Accepted 5 October 2009; Published online 17 November 2009.

Abstract

We investigated glutamate-related neuronal dysfunction in the anterior cingulate (AC) early in schizophrenia before and after antipsychotic treatment. A total of 14 minimally treated schizophrenia patients and 10 healthy subjects were studied with single-voxel proton magnetic resonance spectroscopy (¹H-MRS) of the AC, frontal white matter and thalamus at 4 T. Concentrations of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln) and Gln/Glu ratios were determined and corrected for the partial tissue volume. Patients were treated with antipsychotic medication following a specific algorithm and ¹H-MRS was repeated after 1, 6 and 12 months. There were group region interactions for baseline NAA (P=0.074) and Gln/Glu (P=0.028): schizophrenia subjects had lower NAA (P=0.045) and higher Gln/Glu (P=0.006) in the AC before treatment. In addition, AC Gln/Glu was inversely related to AC NAA in the schizophrenia (P=0.0009) but not in the control group (P=0.92). Following antipsychotic treatment, there were no further changes in NAA, Gln/Glu or any of the other metabolites in any of the regions studied. We conclude that early in the illness, schizophrenia patients already show abnormalities in glutamatergic metabolism and reductions in NAA consistent with glutamate-related excitotoxicity.

The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases

For article, click here.

Perspective

Molecular Psychiatry (2009) 14, 992–1003; doi:10.1038/mp.2009.82

D K Lahiri^1,2, B Maloney¹ and N H Zawia³

1. Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
2. Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
3. Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA

Correspondence: Dr DK Lahiri, Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, 791 Union Drive, Indiana University School of Medicine, Indianapolis, IN 46202, USA. E-mail: dlahiri@iupui.edu

Received 16 February 2009; Revised 29 May 2009; Accepted 17 June 2009.

Top of page

Abstract

Neurobiological disorders have diverse manifestations and symptomology. Neurodegenerative disorders, such as Alzheimer's disease, manifest late in life and are characterized by, among other symptoms, progressive loss of synaptic markers. Developmental disorders, such as autism spectrum, appear in childhood. Neuropsychiatric and affective disorders, such as schizophrenia and major depressive disorder, respectively, have broad ranges of age of onset and symptoms. However, all share uncertain etiologies, with opaque relationships between genes and environment. We propose a 'Latent Early-life Associated Regulation' (LEARn) model, positing latent changes in expression of specific genes initially primed at the developmental stage of life. In this model, environmental agents epigenetically disturb gene regulation in a long-term manner, beginning at early developmental stages, but these perturbations might not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. The LEARn model combines genetic and environmental risk factors in an epigenetic pathway to explain the etiology of the most common, that is, sporadic, forms of neurobiological disorders.

The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases

For article, click here.

Perspective

Molecular Psychiatry (2009) 14, 992–1003; doi:10.1038/mp.2009.82

D K Lahiri^1,2, B Maloney¹ and N H Zawia³

1. ¹Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
2. ²Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
3. ³Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA

Correspondence: Dr DK Lahiri, Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, 791 Union Drive, Indiana University School of Medicine, Indianapolis, IN 46202, USA. E-mail: dlahiri@iupui.edu

Received 16 February 2009; Revised 29 May 2009; Accepted 17 June 2009.

Top of page

Abstract

Neurobiological disorders have diverse manifestations and symptomology. Neurodegenerative disorders, such as Alzheimer's disease, manifest late in life and are characterized by, among other symptoms, progressive loss of synaptic markers. Developmental disorders, such as autism spectrum, appear in childhood. Neuropsychiatric and affective disorders, such as schizophrenia and major depressive disorder, respectively, have broad ranges of age of onset and symptoms. However, all share uncertain etiologies, with opaque relationships between genes and environment. We propose a 'Latent Early-life Associated Regulation' (LEARn) model, positing latent changes in expression of specific genes initially primed at the developmental stage of life. In this model, environmental agents epigenetically disturb gene regulation in a long-term manner, beginning at early developmental stages, but these perturbations might not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. The LEARn model combines genetic and environmental risk factors in an epigenetic pathway to explain the etiology of the most common, that is, sporadic, forms of neurobiological disorders.

Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican

Click here for article.

Original Article

Molecular Psychiatry advance online publication 20 October 2009; doi: 10.1038/mp.2009.92

C Dong¹, M-L Wong² and J Licinio²

1. Department of Psychiatry and Behavioral Sciences, Center for Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL, USA
2. John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia

Correspondence: Professor J Licinio, John Curtin School of Medical Research, The Australian National University, GPO Box 334, Canberra, ACT 2601, Australia. E-mail: julio.licinio@anu.edu.au

Received 20 July 2009; Accepted 28 July 2009; Published online 20 October 2009.

Abstract

We studied seven genes that reflect events relevant to antidepressant action at four sequential levels: (1) entry into the brain, (2) binding to monoaminergic transporters, and (3) distal effects at the transcription level, resulting in (4) changes in neurotrophin and neuropeptide receptors. Those genes are ATP-binding cassette subfamily B member 1 (ABCB1), the noradrenaline, dopamine, and serotonin transporters (SLC6A2, SLC6A3 and SLC6A4), cyclic AMP-responsive element binding protein 1 (CREB1), corticotropin-releasing hormone receptor 1 (CRHR1) and neurotrophic tyrosine kinase type 2 receptor (NTRK2). Sequence variability for those genes was obtained in exonic and flanking regions. A total of 56 280 000 bp across were sequenced in 536 unrelated Mexican Americans from Los Angeles (264 controls and 272 major depressive disorder (MDD)). We detected in those individuals 419 single nucleotide polymorphisms (SNPs); the nucleotide diversity was 0.000540.0001. Of those, a total of 204 novel SNPs were identified, corresponding to 49% of all previously reported SNPs in those genes: 72 were in untranslated regions, 19 were in coding sequences of which 7 were non-synonymous, 86 were intronic and 27 were in upstream/downstream regions. Several SNPs or haplotypes in ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1 and NTRK2 were associated with MDD, and in ABCB1, SLC6A2 and NTRK2 with antidepressant response. After controlling for age, gender and baseline 21-item Hamilton Depression Rating Scale (HAM-D21) score, as well as correcting for multiple testing, the relative reduction of HAM-D21 score remained significantly associated with two NTRK2-coding SNPs (rs2289657 and rs56142442) and the haplotype CAG at rs2289658 (splice site), rs2289657 and rs2289656. Further studies in larger independent samples will be needed to confirm these associations. Our data indicate that extensive assessment of sequence variability may contribute to increase understanding of disease susceptibility and drug response. Moreover, these results highlight the importance of direct re-sequencing of key candidate genes in ethnic minority groups in order to discover novel genetic variants that cannot be simply inferred from existing databases.

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

Click here for paper.

Original Article

Molecular Psychiatry advance online publication 3 November 2009; doi: 10.1038/mp.2009.115

A Neufeld-Cohen¹, A K Evans², D Getselter¹, A Spyroglou³, A Hill³, S Gil¹, M Tsoory¹, F Beuschlein³, C A Lowry², W Vale⁴ and A Chen¹

1. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
2. Department of Integrative Physiology, University of Colorado, Boulder, CO, USA
3. Medical Clinic, University Hospital Innenstadt, Ludwig Maximilians University, Munich, Germany
4. Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA, USA

Correspondence: Dr A Chen, Department of Neurobiology, Weizmann Institute of Science, PO Box 26, Rehovot 76100, Israel. E-mail: alon.chen@weizmann.ac.il

Received 9 January 2009; Revised 21 September 2009; Accepted 23 September 2009; Published online 3 November 2009.

Abstract

The urocortin (Ucn) family of neuropeptides is suggested to be involved in homeostatic coping mechanisms of the central stress response through the activation of corticotropin-releasing factor receptor type 2 (CRFR2). The neuropeptides, Ucn1 and Ucn2, serve as endogenous ligands for the CRFR2, which is highly expressed by the dorsal raphe serotonergic neurons and is suggested to be involved in regulating major component of the central stress response. Here, we describe genetically modified mice in which both Ucn1 and Ucn2 are developmentally deleted. The double knockout mice showed a robust anxiolytic phenotype and altered hypothalamic–pituitary–adrenal axis activity compared with wild-type mice. The significant reduction in anxiety-like behavior observed in these mice was further enhanced after exposure to acute stress, and was correlated with the levels of serotonin and 5-hydroxyindoleacetic acid measured in brain regions associated with anxiety circuits. Thus, we propose that the Ucn/CRFR2 serotonergic system has an important role in regulating homeostatic equilibrium under challenge conditions.

A new mouse model of pediatric autoimmune neuropsychiatric disorders

Click here for the paper.

Original Article

Molecular Psychiatry advance online publication 11 August 2009; doi: 10.1038/mp.2009.77

Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection

K Yaddanapudi 1,2, M Hornig 1,2, R Serge 1, J De Miranda 1, A Baghban 1, G Villar 1 and W I Lipkin 1

1 Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

Correspondence: Dr M Hornig, Center for Infection and Immunity, Mailman School of Public Health,Columbia University, 722 W 168th Street, New York, NY 10032, USA. E-mail: mh2092@columbia.edu

2 These authors contributed equally to this work.

Received 25 February 2009; Revised 11 June 2009; Accepted 15 June 2009; Published online 11 August 2009.

Abstract

Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A beta-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and alpha-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood–brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.

Brains of psychopaths are different

For the Times Online commentary on this Molecular Psychiatry article, click here.

For the original Molecular Psychiatry article, click here.

Original Article

Molecular Psychiatry advance online publication 9 June 2009; doi: 10.1038/mp.2009.40
Altered connections on the road to psychopathy

M C Craig1,2, M Catani1,2, Q Deeley1, R Latham1, E Daly1, R Kanaan3, M Picchioni3, P K McGuire3, T Fahy4 and D G M Murphy1

1. Section of Brain Maturation, Institute of Psychiatry, De Crespigny Park, London, UK
2. Natbrainlab, Institute of Psychiatry, De Crespigny Park, London, UK
3. Section of Neuroimaging, Institute of Psychiatry, De Crespigny Park, London, UK
4. Department of Forensic Mental Health Science, Institute of Psychiatry, De Crespigny Park, London, UK

Correspondence: Dr MC Craig, Psychological Medicine, Institute of Psychiatry, PO50, 16 De Crespigny Park, Denmark Hill, London SE5 8AF, UK. E-mail: m.craig@iop.kcl.ac.uk

Received 7 August 2008; Revised 25 February 2009; Accepted 13 April 2009; Published online 9 June 2009.

Abstract

Psychopathy is strongly associated with serious criminal behaviour (for example, rape and murder) and recidivism. However, the biological basis of psychopathy remains poorly understood. Earlier studies suggested that dysfunction of the amygdala and/or orbitofrontal cortex (OFC) may underpin psychopathy. Nobody, however, has ever studied the white matter connections (such as the uncinate fasciculus (UF)) linking these structures in psychopaths. Therefore, we used in vivo diffusion tensor magnetic resonance imaging (DT-MRI) tractography to analyse the microstructural integrity of the UF in psychopaths (defined by a Psychopathy Checklist Revised (PCL-R) score of greater than or equal to25) with convictions that included attempted murder, manslaughter, multiple rape with strangulation and false imprisonment. We report significantly reduced fractional anisotropy (FA) (P<0.003),>post hoc comparison with a psychiatric control group with a past history of drug abuse and institutionalization. Our findings remained significant. Taken together, these results suggest that abnormalities in a specific amygdala–OFC limbic network underpin the neurobiological basis of psychopathy.

BDNF and depression: the plot thickens

Click here to go to the article.

Original Article

Molecular Psychiatry advance online publication 21 July 2009; doi: 10.1038/mp.2009.67

Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis

MPOpen

D Taliaz, N Stall, D E Dar and A Zangen

Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

Correspondence: Dr A Zangen, Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: a.zangen@weizmann.ac.il

Received 19 December 2008; Revised 29 April 2009; Accepted 15 June 2009; Published online 21 July 2009.

Top of page

Abstract

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.

Biomarkers for Post-partum Depression

For a link to the paper, click here.

Original Article

Molecular Psychiatry advance online publication 7 July 2009; doi: 10.1038/mp.2009.65

Blood mononuclear cell gene expression signature of postpartum depression

R H Segman1, T Goltser-Dubner1,5, I Weiner2,5, L Canetti1, E Galili-Weisstub1, A Milwidsky3,4, V Pablov1, N Friedman2 and D Hochner-Celnikier3,4

1. Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2. School of Computer Science and Engineering, Hebrew University, Jerusalem, Israel

3. Child & Adolescent Psychiatry Unit, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

4. Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Correspondence: Dr RH Segman, Department of Psychiatry, Hadassah-Hebrew University Medical Center, POB 24035 Mount Scopus, Jerusalem 91240, Israel. E-mail: ronense@ekmd.huji.ac.il

5These two authors contributed equally to this work.

Received 25 November 2008; Revised 30 April 2009; Accepted 9 June 2009; Published online 7 July 2009.

Top of page

Abstract

In sorrow thou shalt bring forth children (Genesis 3:16) seems as relevant today, with one of seven mothers afflicted by a depressive episode, constituting the most common medical complication after delivery. Why mothers are variably affected by mood symptoms postpartum remains unclear, and the pathogenesis and early molecular indicators of this divergent outcome have not been described. We applied a case–control design comparing differential global gene expression profiles in blood mononuclear cells sampled shortly after delivery at the time of inception of postpartum depression (PD). Nine antidepressant naive mothers showing high depressive scores and developing a persisting major depressive episode with postpartum onset were compared with 10 mothers showing low depressive scores and no depressive symptoms on prospective follow-up. A distinctive gene expression signature was observed after delivery among mothers with an emergent PD, with a significant overabundance of transcripts showing a high-fold differential expression between groups, and correlating with depressive symptom severity among all mothers. Early expression signatures correctly classified the majority of PD patients and controls. Those developing persisting PD exhibit a relative downregulation of transcription after delivery, with differential immune activation, and decreased transcriptional engagement in cell proliferation, and DNA replication and repair processes. Our data provide initial evidence indicating that blood cells sampled shortly after delivery may harbor valuable prognostic information for identifying the onset of persisting PD. Some of the informative transcripts and pathways may be implicated in the differential vulnerability that underlies depression pathogenesis.

Inherited aspects of cognition become more evident with age

To see original article click here.

Original Article

Molecular Psychiatry advance online publication 2 June 2009; doi: 10.1038/mp.2009.55

The heritability of general cognitive ability increases linearly from childhood to young adulthood

C M A Haworth¹, M J Wright², M Luciano², N G Martin², E J C de Geus³, C E M van Beijsterveldt³, M Bartels³, D Posthuma^3,4,5, D I Boomsma³, O S P Davis¹, Y Kovas¹, R P Corley⁶, J C DeFries⁶, J K Hewitt⁶, R K Olson⁶, S-A Rhea⁶, S J Wadsworth⁶, W G Iacono⁷, M McGue⁷, L A Thompson⁸, S A Hart⁹, S A Petrill⁹, D Lubinski¹⁰ and R Plomin¹

1. King's College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK
2. Queensland Institute of Medical Research, Brisbane, QLD, Australia
3. Faculty of Psychology and Education, Department of Biological Psychology, VU University, Amsterdam, The Netherlands
4. Section of Medical Genomics, VU Medical Centre, Amsterdam, The Netherlands
5. Section of Functional Genomics, Faculty of Earth and Life Science, VU University, Amsterdam, The Netherlands
6. Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA
7. Department of Psychology, University of Minnesota, Minneapolis, MN, USA
8. Department of Psychology, Case Western Reserve University, Cleveland, OH, USA
9. Human Development and Family Science, Ohio State University, Columbus, OH, USA
10. Department of Psychology and Human Development, Vanderbilt University, Nashville, TN, USA

Correspondence: Professor R Plomin, King's College London, Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. E-mail: Robert.Plomin@iop.kcl.ac.uk

Received 6 February 2009; Revised 27 April 2009; Accepted 4 May 2009; Published online 2 June 2009.

Top of page

Abstract

Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite life's 'slings and arrows of outrageous fortune', do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype–environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

Transgenic primates as research tools: now a reality

To see full article - click here

Article

Nature 459, 523-527 (28 May 2009) | doi:10.1038/nature08090; Received 27 September 2008; Accepted 30 April 2009

Generation of transgenic non-human primates with germline transmission

Erika Sasaki¹, Hiroshi Suemizu¹, Akiko Shimada¹, Kisaburo Hanazawa², Ryo Oiwa¹, Michiko Kamioka¹, Ikuo Tomioka^1,3, Yusuke Sotomaru⁵, Reiko Hirakawa^1,3, Tomoo Eto¹, Seiji Shiozawa^1,4, Takuji Maeda^1,4, Mamoru Ito¹, Ryoji Ito¹, Chika Kito¹, Chie Yagihashi¹, Kenji Kawai¹, Hiroyuki Miyoshi⁶, Yoshikuni Tanioka¹, Norikazu Tamaoki¹, Sonoko Habu⁷, Hideyuki Okano⁴ & Tatsuji Nomura¹

1. Central Institute for Experimental Animals, 1430 Nogawa, Miyamae-ku, Kawasaki, Kanagawa 216-0001, Japan
2. Department of Urology, Juntendo University Nerima Hospital 3-1-10 Takanodai, Nerima-ku, Tokyo 177-8521, Japan
3. Center for Integrated Medical Research,
4. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
5. Natural Science Centre for Basic Research and Development, Hiroshima University 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan
6. Subteam for Manipulation of Cell Fate, RIKEN BioResource Centre, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
7. Department of Immunology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan

Correspondence to: Erika Sasaki¹Hideyuki Okano⁴ Correspondence and requests for materials should be addressed to E.S. (Email: esasaki@ciea.or.jp) or H.O. (Email: hidokano@sc.itc.keio.ac.jp).

Top of page

Abstract

The common marmoset (Callithrix jacchus) is increasingly attractive for use as a non-human primate animal model in biomedical research. It has a relatively high reproduction rate for a primate, making it potentially suitable for transgenic modification. Although several attempts have been made to produce non-human transgenic primates, transgene expression in the somatic tissues of live infants has not been demonstrated by objective analyses such as polymerase chain reaction with reverse transcription or western blots. Here we show that the injection of a self-inactivating lentiviral vector in sucrose solution into marmoset embryos results in transgenic common marmosets that expressed the transgene in several organs. Notably, we achieved germline transmission of the transgene, and the transgenic offspring developed normally. The successful creation of transgenic marmosets provides a new animal model for human disease that has the great advantage of a close genetic relationship with humans. This model will be valuable to many fields of biomedical research.

Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder

To see article click here

Original Article

Molecular Psychiatry advance online publication 26 May 2009; doi: 10.1038/mp.2009.50

Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder

M H Bloch¹, J McGuire¹, A Landeros-Weisenberger¹, J F Leckman¹ and C Pittenger²

1. ¹Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA
2. ²Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Correspondence: Dr MH Bloch, Child Study Center, Yale University School of Medicine, PO Box 20709, New Haven, CT 06520, USA. E-mail: Michael.bloch@yale.edu

Received 22 January 2009; Accepted 13 April 2009; Published online 26 May 2009.

Top of page

Abstract

We sought to determine differences in efficacy and tolerability between different doses of selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) using meta-analysis. We identified 9 studies involving 2268 subjects that were randomized, double-blind placebo-controlled clinical trials that compared multiple, fixed-doses of selective serotonin reuptake inhibitors (SSRIs) to each other and to placebo in the treatment of adults with OCD. Change in Y-BOCS score, proportion of treatment responders, and dropouts (all-cause and due to side-effects) were determined for each included study. Weighted mean difference was used to examine mean change in Y-BOCS score. Pooled absolute risk difference was used to examine dichotomous outcomes. Meta-analysis was performed using a fixed effects model in RevMan 4.2.8. We found that compared with either low or medium doses, higher doses of SSRIs were associated with improved treatment efficacy, using either Y-BOCS score or proportion of treatment responders as an outcome. Dose of SSRIs was not associated with the number of all-cause dropouts. Higher doses of SSRIs were associated with significantly higher proportion of dropouts due to side-effects. These results suggests that higher doses of SSRIs are associated with greater efficacy in the treatment of OCD. This SSRI efficacy pattern stands in contrast to other psychiatric disorders like Major Depressive Disorder. This greater treatment efficacy is somewhat counterbalanced by the greater side-effect burden with higher doses of SSRIs. At present, there are insufficient data to generalize these findings to children or adolescents with OCD.

Chromosome 8p: A Review

See article here

Feature Review

Molecular Psychiatry (2009) 14, 563–589; doi:10.1038/mp.2009.2; published online 10 February 2009

Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer

R Tabarés-Seisdedos¹ and J L R Rubenstein²

1. Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, CIBER-SAM, University of Valencia, Valencia, Spain
2. Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA, USA. E-mail: Rafael.Tabares@uv.es

Correspondence: Professor Dr R Tabarés-Seisdedos, Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, University of Valencia, CIBER-SAM, Blasco-Ibáñez 17, 46010 Valencia, Spain; Professor Dr John LR Rubenstein, Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA 94143, USA. E-mail: John.Rubenstein@ucsf.edu

Received 1 August 2008; Revised 19 December 2008; Accepted 7 January 2009; Published online 10 February 2009.

Top of page

Abstract

Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.

The Best on Translational Science

Academic Health Science Centres: a revolution in healthcare?

6 March 2009

King’s Health Partners hosted an international conference on 6 March 2009, discussing ‘Academic Health Science Centres: a revolution in healthcare?’

Presentations followed by question and answer sessions were given from a variety of healthcare and research experts from across the globe, within both public and private sector organisations.

The conference saw over 300 attendees from the UK and further afield, and was opened by Sir Alan Langlands, Principal and Chancellor for the University of Dundee. Other speakers throughout the day included representatives from US healthcare organisations and pharmaceutical companies as well as our own internal specialists in both research and clinical delivery.

The day ended on a positive, with a closing note from Ruth Carnall, Chief Executive for NHS London, whereby she gave her support to all the AHSC applicants, in what will be a positive change for the benefit of patients.

Check this conference on the web and download the presentations. They are really outstanding. Click here.

To see an outstanding Translational Science Center application from the Imperial College of Science, Technology and Medicine, click here.

New findings on the genetics of autism: WGAS points to 5p14.1

To get the pdf of the paper, click here

Source: Nature AOP doi:10.1038/nature07999

Abstract:
Common genetic variants on 5p14.1 associate with autism spectrum disorders

Kai Wang et al.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P53.431028, odd ratio51.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.431028 to 2.1310210. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Personal technology: Phoning in data

For more info click here. 

Far from being just an accessory, mobile phones are starting to be used to collect data in an increasing number of disciplines. Roberta Kwok looks into their potential.

Pre-publication: the effects of stress on decision-making

From Nature Precedings

hdl:10101/npre.2009.2923.1

For link to paper, click here.

Stress impairs decision-making in rats

Lauren K. Jones¹, Taejib Yoon¹, & Jeansok J. Kim²

Correspondence: (Login to view email address)

1. Department of Psychology, University of Washington
2. Department of Psychology and Program in Neurobiology & Behavior, University of Washington

PDF (232.8 KB)

Document Type:

Manuscript

Date:

Received 05 March 2009 02:48 UTC; Posted 05 March 2009

Subjects:

Neuroscience

Tags:

• foraging behaviour
• decision-making
• stress
• rat
• Amygdala

Abstract:

Stress influences various types of memory, but its effects on other cognitive functions are relatively unknown. We investigated the effects of uncontrollable stress on subsequent decision-making in rats, using a computer vision-based water foraging choice task. Stress impaired the animals’ ability to bias their responses toward the larger reward when transitioning from equal to unequal quantities, and this stress effect was dependent on the amygdala.

From SCIENCE: Fear memory in mice is erased by experimental killing of a subpopulation of lateral amygdala neurons

Science 13 March 2009: Vol. 323. no. 5920, pp. 1492 - 1496 DOI: 10.1126/science.1164139

For article, click here.

For podcast interview with author, click here.

Reports

Selective Erasure of a Fear Memory

Jin-Hee Han,^1,2,3 Steven A. Kushner,^1,4 Adelaide P. Yiu,^1,2 Hwa-Lin (Liz) Hsiang,^1,2 Thorsten Buch,⁵ Ari Waisman,⁶ Bruno Bontempi,⁷ Rachael L. Neve,⁸ Paul W. Frankland,^1,2,3 Sheena A. Josselyn^1,2,3*

¹ Program in Neurosciences and Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.
² Institute of Medical Sciences, University of Toronto, Toronto, ON, M5G 1X8, Canada.
³ Department of Physiology, University of Toronto, Toronto, ON, M5G 1X8, Canada.
⁴ Department of Psychiatry, Erasmus University Medical Center, 3015 CE Rotterdam, Netherlands.
⁵ Department of Pathology, University of Zurich, CH-8057 Zurich, Switzerland.
⁶ I.Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, 55131 Mainz, Germany.
⁷ Centre de Neurosciences Intégratives et Cognitives, CNRS UMR5228 and University of Bordeaux 1, 33405 Talence, France.
⁸ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

^* To whom correspondence should be addressed. E-mail: sheena.josselyn@sickkids.ca

Is schizophrenia caused by alterations in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics?

Click here for a link to this article.

Molecular Psychiatry advance online publication 3 March 2009; doi: 10.1038/mp.2009.18

Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function

P R Maycox¹, F Kelly², A Taylor², S Bates², J Reid², R Logendra³, M R Barnes³, C Larminie³, N Jones², M Lennon⁴, C Davies¹, J J Hagan¹, C A Scorer¹, C Angelinetta⁵, T Akbar⁵, S Hirsch⁵, A M Mortimer^5,6, T R E Barnes⁵ and J de Belleroche⁵

1. Psychiatry CEDD, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, UK
2. Genetic and Proteomic Sciences, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, UK
3. Computational Biology, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, UK
4. Statistical Sciences, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, UK
5. Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
6. Academic Unit of Psychiatry, University of Hull, Hull, UK

Correspondence: Professor J de Belleroche, Neurogenetics Group, Division of Neuroscience and Mental Health, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London W12 0NN, UK. E-mail: j.belleroche@imperial.ac.uk

Received 20 October 2008; Revised 27 January 2009; Accepted 28 January 2009; Published online 3 March 2009.

Abstract

Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30 000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. We then compared our study (Charing Cross Hospital prospective collection) with that of an independent prefrontal cortex dataset from the Harvard Brain Bank. We report the first direct comparison between two independent studies. A total of 51 gene expression changes have been identified that are common between the schizophrenia cohorts, and 49 show the same direction of disease-associated regulation. In particular, changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics. This strongly suggests multiple, small but synergistic changes in gene expression that affect nerve terminal function.

Is the neurogenesis hypothesis of depression and antidepressant action only applicable to the young?

Click here for a link to this article.

Molecular Psychiatry advance online publication 13 January 2009; doi: 10.1038/mp.2008.147

Ageing abolishes the effects of fluoxetine on neurogenesis

S Couillard-Despres¹, C Wuertinger¹, M Kandasamy¹, M Caioni¹, K Stadler¹, R Aigner¹, U Bogdahn¹ and L Aigner^1,2

1. Department of Neurology, University of Regensburg, Regensburg, Germany
2. Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria

Correspondence: Dr S Couillard-Despres, Department of Neurology, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg D-93053, Germany. E-mail: sebastien.couillard-despres@klinik.uni-regensburg.de

Received 9 July 2008; Revised 26 November 2008; Accepted 15 December 2008; Published online 13 January 2009.

Abstract

Depression constitutes a widespread condition observed in elderly patients. Recently, it was found that several drugs employed in therapies against depression stimulate hippocampal neurogenesis in young rodents and nonhuman primates. As the rate of neurogenesis is dramatically reduced during ageing, we examined the influences of ageing on neurogenic actions of antidepressants. We tested the impact of fluoxetine, a broadly used antidepressant, on hippocampal neurogenesis in mice of three different age groups (100, 200 and over 400 days of age). Proliferation and survival rate of newly generated cells, as well as the percentage of cells that acquired a neuronal phenotype were analyzed in the hippocampus of mice that received fluoxetine daily in a chronic manner. Surprisingly, the action of fluoxetine on neurogenesis was decreasing as a function of age and was only significant in young animals. Hence, fluoxetine increased survival and the frequency of neuronal marker expression in newly generated cells of the hippocampus in the young adult group (that is 100 days of age) only. No significant effects on neurogenesis could be detected in fluoxetine-treated adult and elderly mice (200 and over 400 days of age). The data indicate that the action of fluoxetine on neurogenesis is highly dependent on the age of the treated individual. Although the function of neurogenesis in the clinical manifestation of depression is currently a matter of speculation, this study clearly shows that the therapeutic effects of antidepressants in elderly patients are not mediated by neurogenesis modulation.

Adolescent alcohol use: an interaction of parenting and dopamine D2 genotype?

Click here for a link to this article.

Molecular Psychiatry advance online publication 24 February 2009; doi: 10.1038/mp.2009.4

Interaction between dopamine D2 receptor genotype and parental rule-setting in adolescent alcohol use: evidence for a gene-parenting interaction

C S van der Zwaluw¹, R C M E Engels¹, A A Vermulst¹, B Franke^2,3, J Buitelaar³, R J Verkes³ and R H J Scholte¹

1. Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands
2. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3. Department of Psychiatry, Radboud University Nijmegen Medical Centre, Donders Centre for Neuroscience, Nijmegen, The Netherlands

Correspondence: CS van der Zwaluw, Behavioral Science Institute, Radboud University Nijmegen, PO Box 9104, 6500 HE Nijmegen, The Netherlands. E-mail: C.vanderZwaluw@bsi.ru.nl

Received 22 September 2008; Revised 3 December 2008; Accepted 18 December 2008; Published online 24 February 2009.

Abstract

Association studies investigating the link between the dopamine D2 receptor gene (DRD2) and alcohol (mis)use have shown inconsistent results. This may be due to lack of attention for environmental factors. High levels of parental rule-setting are associated with lower levels of adolescent alcohol use and delay of initiation of drinking. We tested whether DRD2 TaqI A (rs1800497) genotype interacts with alcohol-specific parenting practices in predicting the uptake of regular adolescent alcohol use. Non-regular drinkers were selected from a Dutch, nationwide sample of 428 adolescents (mean age 13.4 years at baseline) and participated in a prospective, community-based study with three annual waves. Parental rule-setting was directly and inversely related to adolescent alcohol use over time. For DRD2 genotype no significant main effect was found. DRD2 genotype interacted with parental rule-setting on adolescent alcohol use over time: adolescents, with parents highly permissive toward alcohol consumption and carrying a genotype with the DRD2 A1 (rs1800497T) allele, used significantly more alcohol over time than adolescents without these characteristics. The DRD2 genotype may pose an increased risk for alcohol use and abuse, depending on the presence of environmental risk factors, such as alcohol-specific parenting.

Prenatal cigarette exposure and genes: a pathway to sociopathy

Click here for a link to this article.

Molecular Psychiatry advance online publication 3 March 2009; doi: 10.1038/mp.2009.22

Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior

L S Wakschlag¹, E O Kistner², D S Pine³, G Biesecker¹, K E Pickett⁴, A D Skol⁵, V Dukic², R J R Blair³, B L Leventhal¹, N J Cox⁵, J L Burns¹, K E Kasza², R J Wright⁶ and E H Cook Jr¹

1. Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
2. Department of Health Studies, University of Chicago, Chicago, IL, USA
3. Laboratory of Affective & Developmental Neurosciences, NIMH Intramural Research Program, Bethesda, MD, USA
4. Department of Health Sciences, University of York, York, England
5. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
6. Channing Laboratory, Harvard University Medical School, Boston, MA, USA

Correspondence: Dr LS Wakschlag, Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, 1747 W. Roosevelt Road, MC747, Chicago, IL 60608, USA. E-mail: lwakschlag@psych.uic.edu

Received 2 October 2008; Revised 29 January 2009; Accepted 3 February 2009; Published online 3 March 2009.

Abstract

Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene exposure mechanisms requires precise measurement of exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene exposure interaction was detected. Exposed boys with the low-activity MAOA 5' uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene–environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene exposure interactions may shape behavior through associated changes in brain function.