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

Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L, Li C, Folstein SE, Blakely RD
Am J Hum Genet. 2005 77 (2): 265-79

PMID: 15995945 · PMCID: PMC1224529 · DOI:10.1086/432648

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 17q11.2, 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.

MeSH Terms (30)

Alanine Alleles Autistic Disorder Blood Platelets Chromosomes, Human, Pair 17 Compulsive Behavior Exons Family Health Female Gene Deletion Genetic Linkage Genetic Markers Genetic Predisposition to Disease Glycine Humans Introns Linkage Disequilibrium Male Membrane Glycoproteins Membrane Transport Proteins Models, Genetic Nerve Tissue Proteins Pedigree Phenotype Polymorphism, Genetic Polymorphism, Single Nucleotide Risk Serotonin Serotonin Plasma Membrane Transport Proteins Time Factors

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