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Autism and the serotonin transporter: the long and short of it

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.

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Acknowledgements

This research was funded by program project grants from the National Institute of Child Health and Human Development and the National Institute on Deafness and Communication Disability (U19 HD035465, U19 HD35482, U19 HD035469, U19 HD035466), which are part of the NICHD/NIDCD Collaborative Program of Excellence in Autism. BD was supported by MH057881. Work at the University of Utah was supported by PO1 HD35476 to WMN, and Public Health Service research Grant M01-RR00064 from the National Center for Research and Resources and the Devonshire Foundation. Work at the University of Rochester was also conducted in the General Clinical Research Center, which is supported in part by a grant from the National Center for Research Resources, M01-RR00044. Work at the University of Washington and the Seattle Veterans Affairs Medical Center was supported by the Department of Veterans Affairs. We thank Elaine Loomis, Vibhor Sonpar, Shawn Wood, and Weiting Xie for their excellent technical support.

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Correspondence to G D Schellenberg.

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Supplementary Information accompanies the paper on Molecular Psychiatry website (http://www.nature.com/mp).

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Devlin, B., Cook, E., Coon, H. et al. Autism and the serotonin transporter: the long and short of it. Mol Psychiatry 10, 1110–1116 (2005). https://doi.org/10.1038/sj.mp.4001724

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