Allelic Heterogeneity at the Serotonin Transporter Locus (SLC6A4) Confers Susceptibility to Autism and Rigid-Compulsive Behaviors

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 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.

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…The most common assessed variants are a deletion/ insertion polymorphism in the transcriptional control region of the SLC6A4 gene with functional effects (5HTTLPR) [227][228][229] and a variable number of tandem repeat in intron 2 (STin2). Several studies have found an association of the short alleles of 5HTTLPR with AD, 217,[230][231][232][233] fewer studies of the long alleles. 234,235 Some studies did not replicate these findings.…”

Functional SLITRK1 var321, varCDfs and SLC6A4 G56A variants and susceptibility to obsessive-compulsive disorder

“…1,2 Here, we investigated these gene variants in obsessivecompulsive disorder (OCD), based on high degrees of TS/OCD comorbidity, plus G56A functionally resembling SLC6A4 I425 V in producing transporter gain-offunction. [2][3][4] SLITRK1 was uncovered as a candidate for TS owing to its < 230 kb proximity to a breakpoint of a 13q chromosomal inversion found in a child with TS and attention-deficit/hyperactivity disorder (ADHD), in addition to its role in neurite outgrowth.…”

“…1,2 Here, we investigated these gene variants in obsessivecompulsive disorder (OCD), based on high degrees of TS/OCD comorbidity, plus G56A functionally resembling SLC6A4 I425 V in producing transporter gain-offunction. [2][3][4] SLITRK1 was uncovered as a candidate for TS owing to its < 230 kb proximity to a breakpoint of a 13q chromosomal inversion found in a child with TS and attention-deficit/hyperactivity disorder (ADHD), in addition to its role in neurite outgrowth. 1 Furthermore, screening of 174 additional TS probands for SLITRK1 variants revealed a truncating frameshift mutation, varCDfs, with complete loss of function in one, and a microRNA domain-affecting variant, var321, which leads to reduced reporter gene activity in vitro, in two other of these probands (Table 1).…”

“…11 Another rare coding SLC6A4 variant, G56A, has recently been suggested to confer susceptibility to autism with predominantly rigid-compulsive symptomatology in an autism multiplex family study that also demonstrated a strong linkage analysis peak near the SLC6A4 gene for male, but not for female, probands. 2 Both the I425 V and the G56A variants have been shown to lead to an increased serotonin transporter protein activity in transfected cell lines. [2][3][4] In the same population of our 322 OCD probands and 390 controls, allelic frequencies for G56A (Table 2) did not differ significantly between probands and controls and are in agreement with previous reports.…”

“…2 Both the I425 V and the G56A variants have been shown to lead to an increased serotonin transporter protein activity in transfected cell lines. [2][3][4] In the same population of our 322 OCD probands and 390 controls, allelic frequencies for G56A (Table 2) did not differ significantly between probands and controls and are in agreement with previous reports. 2,12 We identified one Ala56 homozygote in the US Caucasian control population (Coriell NA17267); all other Ala56 alleles occurred as heterozygotes.…”