Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism

Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
Neuropsychopharmacology (Impact Factor: 7.83). 02/2008; 33(2):353-60. DOI: 10.1038/sj.npp.1301406
Source: PubMed

ABSTRACT Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (K(m), p=0.005) and 5-HT uptake rate (V(max), p=0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p=0.046). These initial studies of indices of the 5-HT system with several single-nucleotide polymorphisms at loci in this system generate hypotheses for testing in other samples.

  • Source
    • "Hyperserotonemia is indeed the most consistent neurochemical change in autism [7] [8] [9] [10] [11]. Hyperserotonemia is also found in firstdegree relatives [12] and is associated with recurrence risk of autism within families [13] [14] [15]. It is important to keep in mind that in the mature brain, blood levels of serotonin are not an indicator of brain serotonin, because (1) serotonin does not cross the mature blood brain barrier (BBB) and (2) the synthetic enzyme tryptophan hydroxylase is different in the brain and in the periphery [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of autism, a neurodevelopmental condition resulting from genetic and environmental causes, has increased dramatically during the last decade. Among the potential environmental factors, hyperserotonemia during pregnancy and its effect on brain development could be playing a role in this prevalence raise. In the rodent model developed by Whitaker-Azmitia and colleagues, hyperserotonemia during fetal development results in a dysfunction of the hypothalamo-pituitary axis, affecting the amygdala as well as pro-social hormone oxytocin regulation. Dysfunction of the amygdala and abnormal oxytocin levels may underlie many clinical features of ASD. Selective serotonin reuptake inhibitors (SSRI) are the most widely used class of antidepressants drugs, and they are not contraindicated during pregnancy. In this paper, we hypothesize that increased serotonemia during pregnancy, including due to SSRI intake, could be one of the causes of the raising prevalence in autism. If our hypothesis is confirmed, it will not only shed light on one of the possible reason for autism prevalence, but also offer new preventive and treatment options.
    Medical Hypotheses 12/2009; 74(5):880-3. DOI:10.1016/j.mehy.2009.11.015 · 1.07 Impact Factor
  • Source
    • "This developmental effect may be the mechanism by which TPH1 influences CNS serotonergic functioning in adult brain, thereby affect behavior and psychopathology in adulthood. While there are no studies examining the developmental effect of TPH1 polymorphisms, a recent study of the relationship between TPH1 and whole blood serotonin levels in family members of children with autism reported a moderate association with a TPH1 two-SNP haplotype that included the A779C polymorphism (Cross et al., 2008). Results showed that the haplotype under study, which included the A allele of the A779C polymorphism, was associated with increased serotonin levels in a dose-dependent manner, and suggest that TPH1 polymorphisms could also have an effect on prenatal serotonin levels as well. "
    [Show abstract] [Hide abstract]
    ABSTRACT: While there is some preliminary evidence that the tryptophan hydroxylase I (TPH1) polymorphisms are related to Borderline Personality Disorder (BPD), it is not clear if this association is due to the high rates of suicidal behavior in this patient group. Because of the reported association between TPH1 polymorphisms and suicidal behavior, determining whether TPH1 is related to BPD independent of suicidal behavior is of particular importance. One hundred patients diagnosed with BPD and 101 healthy controls were genotyped for TPH1 intron 7 A218C polymorphism and assessed for impulsiveness and hostility. The BPD patient group had a higher frequency of A allele carriers (AA/AC genotypes) than the control group (chi(2) = 6.12, df = 1, P = 0.01), and differed by genotype frequencies (P = 0.03). Suicide attempter status in the patient group was not related to genotype. Logistic regression analysis controlling for age and gender predicted BPD diagnosis from TPH1 allele group (AA/AC vs. CC, P = 0.03), and TPH1 heterozygotes (AC) appeared to have the highest risk for BPD (P = 0.03). In the full sample, participants with the AC genotype had higher impulsiveness and hostility scores. However, TPH1 did not predict these traits in either of the groups independently, suggesting the association may be an artifact of the association between TPH1 and BPD. Results suggest that the A allele of the tryptophan hydroxylase-1 A218 polymorphism may be associated with BPD, and that it does not appear to be related to suicidal behavior in this population. An aspect of BPD pathology may be due to serotonergic dysfunction.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2009; 150B(2):202-8. DOI:10.1002/ajmg.b.30788 · 3.27 Impact Factor
  • Source
    • "Although it was a secondary analysis, the refined genotype expression groups that included consideration of the TT/TT diplotype revealed the refined low expression group's response was poorer than the intermediate and high expression groups. This is consistent with previous research demonstrating that the presence of the intron 1 TT/TT diplotype leads subjects with S/S and S/L genotypes to have platelet 5HT uptake Vmax more consistent with that of L/L genotype groups(Cross et al., 2007). It is unlikely that that diplotype is functional and more likely that the intron 1 haplotype is in linkage disequilibrium with a functional element increasing expression of the serotonin transporter gene. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To determine the effect of serotonin transporter polymorphism promoter region (5-HTTPLR) genotypic variation (low, intermediate, and high expression groups) on response to escitalopram treatment of children and adolescents with autism spectrum disorders (ASDs). The study used a forced titration, open label design, with genotype blind until study completion. Participants were children and adolescents aged 4-17 years of age with a confirmed ASD (autistic disorder, Asperger's disorder, or pervasive developmental disorder, not otherwise specified). There was an interaction between genotype group and time on the Aberrant Behavior Checklist (ABC) Irritability Subscale (primary outcome variable) (linear maximum marginal likelihood estimation=-4.84, Z=-2.89, SE=1.67, P=0.004). Examination of baseline to last visit revealed that a genotype grouping based on a previous study of platelet 5-HT uptake revealed less response in the genotype group that had S/S genotype for 5-HTTLPR and did not have a diplotype in intron 1 previously shown to be associated with increased platelet 5-HT uptake. This genotype-blind, prospective pharmacogenetic study found the group of subjects with associated with the lowest platelet 5-HT uptake from previous study had the smallest reduction in ABC-Irritability scores after open label treatment with escitalopram. Replication is necessary to confirm these findings.
    Autism Research 01/2009; 3(1):1-7. DOI:10.1002/aur.109 · 4.53 Impact Factor
Show more