Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism
Open Access
- 1 March 2004
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Psychiatry
- Vol. 9 (3), 264-271
- https://doi.org/10.1038/sj.mp.4001409
Abstract
The role of the serotonin system in the etiology and pathogenesis of autism spectrum disorders (ASD) is not clearly defined. High levels of platelet serotonin (5-HT) have been consistently found in a proportion of patients, and it is known that specific 5-HT transporter gene (SLC6A4) variants modulate transporter reuptake function, therefore possibly influencing the occurrence of hyperserotonemia in a subset of autistic patients. We have examined the association of platelet serotonin levels with two SLC6A4 polymorphisms, 5-HTT gene-linked polymorphic region (HTTLPR) in the promoter and intron 2 variable number of tandem repeats (VNTR), in a sample of 105 ASD patients, their parents, and 52 control children. Quantitative transmission disequilibrium test (QTDT) results showed a significant effect on 5-HT levels of each SLC6A4 marker (P=0.017 for HTTLPR; P=0.047 for intron 2 VNTR) and of haplotypes of the two markers (P=0.017), with a major contribution of the L.Stin2.10 haplotype (P=0.0013). A 5-HT mean value in the range of hyperserotonemia was associated with the homozygous L.Stin2.10 haplotype (H (1,N=97)=7.76, P=0.0054), which occurred in 33% of hyperserotonemic patients against 6% of patients with normal 5-HT levels (Fisher's exact test: P=0.013, OR=8). Allele interaction at the HTTLPR locus was found, with a significant dominance variance effect on 5-HT levels. We found no transmission disequilibrium of any of the SLC6A4 variants in ASD. Our results show that the SLC6A4 gene is a significant factor in the determination of 5-HT levels, and that specific SLC6A4 variants are associated with an increased risk for hyperserotonemia in our sample of autistic patients. The biological mechanism, however, is unlikely to involve the SLC6A4 gene solely. The associated SLC6A4 alleles likely interact with other genes or environmental factors to produce the abnormally high 5-HT levels observed in this subset of autistic patients, who possibly represent a separate etiological group.This publication has 43 references indexed in Scilit:
- Serotonin Transporter Genetic Variation and the Response of the Human AmygdalaScience, 2002
- FOXP2 Is Not a Major Susceptibility Gene for Autism or Specific Language ImpairmentAmerican Journal of Human Genetics, 2002
- Phenotypic Homogeneity Provides Increased Support for Linkage on Chromosome 2 in Autistic DisorderAmerican Journal of Human Genetics, 2002
- Genetics of austim: complex aetiology for a heterogeneous disorderNature Reviews Genetics, 2001
- Evidence for a Susceptibility Gene for Autism on Chromosome 2 and for Genetic HeterogeneityAmerican Journal of Human Genetics, 2001
- Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood plateletsAmerican Journal of Medical Genetics, 1999
- Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory RegionScience, 1996
- Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligenceThe Journal of Neuropsychiatry and Clinical Neurosciences, 1990
- Elevated blood serotonin in autistic probands and their first-degree relativesJournal of Autism and Developmental Disorders, 1989
- Genetic control of serotonin uptake in blood platelets: A twin studyPsychiatry Research, 1988