1. ¹Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
2. ²Department of Psychiatry, Institute for Juvenile Research, University of Illinois, Chicago, IL, USA
3. ³Division of Child and Adolescent Psychiatry, Department of Psychiatry, University of Utah, Salt Lake, UT, USA
4. ⁴Department of Psychology, University of Washington, Seattle, WA, USA
5. ⁵Child Study Center and Department of Psychology, Yale University School of Medicine, Yale University, New Haven, CT, USA
6. ⁶Unit of Psychiatric and Neurodevelopmental Genetics, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
7. ⁷Department of Pediatrics, University of California, Irvine, CA, USA
8. ⁸Department of OB/GYN, University of Rochester Medical Center, Rochester NY, USA
9. ⁹Veterans Affairs Medical Center, Seattle, WA, USA
10. ¹⁰Departments of Medicine, Neurology and Pharmacology, University of Washington, Seattle, WA, USA

Correspondence: Dr GD Schellenberg, Veterans Affairs Medical Center (182b), 1660 S. Columbian RoadM, Seattle, WA 98108, USA. E-mail: zachdad@u.washington.edu

¹¹Members of the Collaborative Programs of Excellence in Autism (CPEA) Genetics Network: Pamela Bennett, Janet Lainart, University of Utah; Julienne Escamilla, University of California, Irvine; Robert Abbott, Annette Estes, Jeffrey Munson, Chang-En Yu, University of Washington.

Received 19 October 2004; Revised 17 June 2005; Accepted 20 June 2005; Published online 16 August 2005.

Abstract

Autism is a neurodevelopmental disorder manifesting early in childhood. Some symptoms of autism are alleviated by treatment with selective serotonin reuptake inhibitors, which are known to interact with the serotonin transporter. Moreover, variation in the gene that encodes the transporter (SLC6A4), especially the HTTLPR locus, is known to modulate its expression. It is natural, therefore, to evaluate whether this variation plays a role in liability to autism. We investigated the impact of alleles at HTTLPR and three other loci in SLC6A4 by using a large, independent family-based sample (390 families, 1528 individuals) from the NIH Collaborative Programs of Excellence in Autism (CPEA) network. Allele transmissions to individuals diagnosed with autism were biased only for HTTLPR, both for the narrow diagnosis of autism (P=0.035) and for the broader diagnosis of autism spectrum (P=0.007). The short allele of HTTLPR was significantly overtransmitted. Investigation of haplotype transmissions suggested that, in our data, biased transmission was only due to HTTLPR. With respect to this locus, there are now seven of 12 studies reporting significant transmission bias of HTTLPR alleles, a noteworthy result in itself. However, the studies with significant findings are almost equally divided between overtransmission of short and overtransmission of long alleles. We place our results within this extremely heterogeneous field of studies. Determining the factors influencing the relationship between autism phenotypes and HTTLPR variation, as well as other loci in SLC6A4, could be an important advance in our understanding of this complex disorder.