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Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder

Molecular Psychiatry volume 7, pages 278–288 (2002)Cite this article

Abstract

The serotonin transporter gene (SLC6A4, MIM 182138) is 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. An insertion/deletion polymorphism (5-HTTLPR) in the promoter region and a variable number of tandem repeat polymorphism (VNTR) in the second intron, were previously identified and suggested to modulate transcription. Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium. In the present study, TDT was conducted in 81 new trios. A previous finding of transmission disequilibrium between a haplotype consisting of the 5-HTTLPR and intron 2 VNTR was replicated in this study, but not preferential transmission of 5-HTTLPR as an independent marker. Because of inconsistent transmission of 5-HTTLPR across studies, 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 115 autism trios. When individual markers were analyzed by TDT, seven SNP markers and four SSR markers (six SNPs, 5-HTTLPR and the second intron VNTR from promoter 1A through intron 2 of SLC6A4, one SSR from intron 7 of SLC6A4, one SNP from the bleomycin hydrolase gene (BLMH, MIM 602403) and one SSR telomeric to BLMH) showed nominally significant evidence of transmission disequilibrium. Four markers showed stronger evidence of transmission disequilibrium (TDTmax P = 0.0005) than 5-HTTLPR.

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Acknowledgements

Zhi-Ying Yang and David Gonen provided expert technical assistance. Nicole Felix and Nelson Ayuyao provided database technical assistance. Jane Nofer, Marrea Winega, Susan Risi, Elisa Steele, Kathleen Kennedy Martin, Alan Lincoln, Senia Pizzo, and Richard Haas contributed to diagnostic assessments of probands. The study was supported in part by NIH R01 MH52223 (EHC, EC), K02 MH01389 (EHC), R01 NS19855 (EC), P01 HD35482 (EHC, CL), the Jean Young and Walden W Shaw Foundation (BLL), and the Irving B Harris Foundation (BLL). S-J Kim was a Daniel X Freedman Psychiatric Research Fellow during the course of this study.

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Author notes

  1. C Corsello & S Guter

    Present address: University of Michigan Autism and Communication Disorders Center, Ann Arbor, MI, USA

Authors and Affiliations

  1. Department of Psychiatry MC3077, Laboratory of Developmental Neuroscience, Child and Adolescent Psychiatry, University of Chicago, Chicago, IL, USA

    S-J Kim, B L Leventhal & E H Cook Jr

  2. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    N Cox

  3. Laboratory for Research on the Neuroscience of Autism, Children's Hospital Research Center, La Jolla, CA, USA

    R Courchesne, N Akshoomoff & E Courchesne

  4. Department of Psychiatry MC3077, Developmental Disorders Clinic, Child and Adolescent Psychiatry, University of Chicago, Chicago, IL, USA

    C Lord, C Lord, C Corsello & S Guter

  5. Department of Pediatrics MC3077, University of Chicago, Chicago, IL, USA

    B L Leventhal & E H Cook Jr

  6. Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA

    E Courchesne

  7. Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, USA

    N Akshoomoff

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Kim, SJ., Cox, N., Courchesne, R. et al. Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder. Mol Psychiatry 7, 278–288 (2002). https://doi.org/10.1038/sj.mp.4001033

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