Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors.
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.
Sutcliffe
James S
JS
Center for Molecular Neuroscience, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-0615, USA. james.s.sutcliffe@vanderbilt.edu
Delahanty
Ryan J
RJ
Prasad
Harish C
HC
McCauley
Jacob L
JL
Han
Qiao
Q
Jiang
Lan
L
Li
Chun
C
Folstein
Susan E
SE
Blakely
Randy D
RD
D000409:Alanine / Q000235:genetics; D000483:Alleles; D001321:Autistic Disorder / Q000235:genetics*; D001792:Blood Platelets / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17; D003192:Compulsive Behavior / Q000235:genetics*; D005091:Exons; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005998:Glycine / Q000235:genetics; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013997:Time Factors
D005819:Genetic Markers; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D000409:Alanine; D005998:Glycine