Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors

James S. Sutcliffe, Ryan J. Delahanty, Harish C. Prasad, Jacob L. McCauley, Qiao Han, Lan Jiang, Chun Li, Susan E. Folstein, Randy D. Blakely

Research output: Contribution to journalArticle

283 Scopus citations

Abstract

Autism is a spectrum of neurodevelopmental disorders with a primarily genetic etiology exhibiting deficits in (1) development of language and (2) social relationships and (3) patterns of repetitive, restricted behaviors or interests and resistance to change. Elevated platelet serotonin (5-HT) in 20%-25% of cases and efficacy of selective 5-HT reuptake inhibitors (SSRIs) in treating anxiety, depression, and repetitive behaviors points to the 5-HT transporter (5-HTT; SERT) as a strong candidate gene. Association studies involving the functional insertion/deletion polymorphism in the promoter (5-HTTLPR) and a polymorphism in intron 2 are inconclusive, possibly because of phenotypic heterogeneity. Nonetheless, mounting evidence for genetic linkage of autism to the chromosome 17q11.2 region that harbors the SERT locus (SLC6A4) supports a genetic effect at or near this gene. We confirm recent reports of sex-biased genetic effects in 17q by showing highly significant linkage driven by families with only affected males. Association with common alleles fails to explain observed linkage; therefore, we hypothesized that preferential transmission of multiple alleles does explain it. From 120 families, most contributing to linkage at I7q11.2, we found four coding substitutions at highly conserved positions and 15 other variants in 5′ noncoding and other intronic regions transmitted in families exhibiting increased rigid-compulsive behaviors. In the aggregate, these variants show significant linkage to and association with autism. Our data provide strong support for a collection of multiple, often rare, alleles at SLC6A4 as imposing risk of autism.

Original languageEnglish (US)
Pages (from-to)265-279
Number of pages15
JournalAmerican journal of human genetics
Volume77
Issue number2
DOIs
StatePublished - Aug 2005

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Sutcliffe, J. S., Delahanty, R. J., Prasad, H. C., McCauley, J. L., Han, Q., Jiang, L., Li, C., Folstein, S. E., & Blakely, R. D. (2005). Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. American journal of human genetics, 77(2), 265-279. https://doi.org/10.1086/432648