ARTICLES
1) "Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorderÓ
AUTHORS: S-J Kim, N Cox, R Courchesne, C Lord, C Corsello, N Akshoomoff, S Guter, BL Leventhal, E Courchesne and EH Cook Jr.
Laboratory of Developmental Neuroscience, Child and Adolescent Psychiatry, Department of Psychiatry MC3077, University of Chicago, Chicago, IL, USA; Department of Human Genetics, University of Chicago, Chicago, IL, USA; Laboratory for Research on the Neuroscience of Autism, ChildrenÕs Hospital Research Center, La Jolla, CA, USA; Developmental Disorders Clinic, Child and Adolescent Psychiatry MC3077, University of Chicago, Chicago, IL, USA (currently at University of Michigan Autism and Communication Disorders Center, Ann-Arbor, MI, USA); Department of pediatrics MC3077, University of Chicago, Chicago, IL, USA; Department of Neurosciences School of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, USA
The authors discuss the serotonin transporter gene SLC6A4 as a candidate gene in autistic disorder based on neurochemical, neuroendocrine studies and the efficacy of potent serotonin transporter inhibitors in reducing ritualistic behaviors and related aggression. SLC6A4 and its flanking regions were sequenced in 10 probands, followed by typing of 20 single nucleotide polymorphisms (SNPs) and seven simple sequence repeat (SSR) polymorphisms in 155 autism trios. Four markers showed stronger evidence of transmission disequilibrium (TDTmax P=0.0005) than 5-HTTLPR. It will be important to see if those newly identified variants lead to more consistent results across autism samples and whether they help in understanding the variable association with other phenotypes ranging from neuroticism to bipolar mood disorder.
Citation source: Molecular Psychiatry 2002 Volume 7, number 3, pages 278-288.
For further information on this work, please contact Dr. Edwin Cook, Department of Psychiatry, MC 3077, 5841 S. Maryland Avenue, Chicago, Illinios 60637; phone: (773) 702- 9692; FAX: (773) 834-2970; e-mail: ed@yoda.bsd.uchicago.edu
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2) "Mutation screening and imprinting analysis of four candidate genes for autism in the 7q32 regionÓ
AUTHORS: E Bonora, E Bacchelli, ER Levy, F Blasi, A Marlow, AP Monaco, E Maestrini, and the International Molecular genetic Study of Autism Consortium (IMGSAC).
The Wellcome Trust Centre for Human genetics, University of Oxford, Oxford, UK; University of Bologna, Dipartimento of Biologia Evoluzionistica, Bologna, Italy
This article focuses on genetic studies that suggest chromosome 7q as a likely host for an autism susceptibility locus (AUTS1). The authors follow a positional candidate gene approach to identify the gene in question and report the analysis of four adjacent genes localized to a 800-kb region in 7q32 that contain an imprinted domain Ð a previously uncharacterized member of the carboxypeptidase gene family. The analysis of these genes strongly suggests that they do not play a major role in autism and delineate the strategy to screen additional candidate genes in the AUTS1 locus.
Citation source: Molecular Psychiatry 2002 Volume 7, number 3, pages 289-301.
For further information on this work, please contact Dr. Elena Maestrini, University of Bologna, Dipartimento di Biologia Evoluzionistica Sperimentale, via Selmi 3, Bologna, Italy 40126; phone: 39 51 209 4178; e-mail: maestrin@alma.unibo.it
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3) "Linkage and association of the glutamate receptor 6 gene with autismÓ
AUTHORS: S Jamain, C Betancuf, H Quach, A Phillipe, M Fellous, B Giros, C Gillberg, M Leboyer, T Bourgeron and the Paris Autism Research International Sibpair (PARIS) Study.
Laboratoire dÕImmunogenetique Humaine, INSERM E021, Institut Pasteur, 75015 Paris, france, INSERM U513, Faculte de Medecine de Creteil, 94000 Creteil, France; Department of Child and Adolescent Psychiatry, Goteborg University, 41119 Goteborg, Sweden, Department of Psychiatry, Hopital Albert Chenevier et Henri Mondor , 94000 Creteil, France
The authors present the results of a genome scan that point to chromosome 6q21 as a candidate region for autism, an area containing the glutamate receptor 6 (GluR6 or GRIK2) gene, which is known as a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. The authors used two approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method was conducted with additional markers on 51 original families and in eight new sibling pairs. Results revealed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis performed in the ASP families, and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis with only affected proband per family showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs) including one amino acid change (M867I) in a highly conserved domain of the intractyplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population, indicating a more maternal transmission than expected as compared to autistic males (P = 0.007). All together, these data suggest that GluR6 is in linkage disequilibrium with autism.
Citation source: Molecular Psychiatry 2002 Volume 7, number 3, pages 302-310.
For further information on this work, please contact Dr. Thomas Bourgeron, Laboratoire dÕImmunogenetique Humaine, INSERM E021, Institute Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France; e-mail: thomasb@pasteur.fr
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4) "Association between a GABRB3 polymorphism and autismÓ
AUTHORS: JD Buxbaum, J Silverman, CJ Smith, DA Greenberg, M Kilifarski, J Reichert, EH Cook Jr, Y Fang, C-Y Song, R Vitale.
Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA; Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA; Department of Neurobiology, Mount Sinai School of Medicine, New York, NY 10029, USA; Seaver Autism research Center, Mount Sinai School of Medicine, New York, NY 10029, USA; Laboratory of Developmental Neuroscience and Developmental Disorders Clinic, Departments of Psychiatry and Pediatrics, University of Chicago, Chicago, IL 60637, USA
This paper discusses the results of an association analysis, examining the 155CA-2 gene using the Transmission Disequilibrium Test (TDT) in a set of 80-autism-affected families (59 multiplex and 21 trios). In addition, the authors applied four additional markers localized within 150 kb of the 155CA-2 gene. The use of multi-allelic TDT (MTDT) (P<0.002) as well as the TDT (P<0.004) demonstrated an association between autistic disorder and the 155CA-2 gene in these families. These findings support a role for genetic variants within the GABA receptor gene complex at the 15q11-13 region in autistic children.
Citation source: Molecular Psychiatry 2002 Volume 7, number 3, pages 311-316.
For further information on this work, please contact Dr. Joseph Daniel Buxbaum, Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L Levy place, Box 1230, New York, NY 10029; e-mail: buxbaj01@doc.mssm.edu
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Editor: Julio Licinio, M.D.; phone: +1 310 825-7113; FAX: +1 310 206-6715; e-mail: licinio@ucla.edu
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Molecular Psychiatry