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

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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.

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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

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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

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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.