Serotonin transporter gene promoter variants do not explain the hyperserotoninemia in autistic children

Abstract

Autism is a biologically-heterogeneous disease. Distinct subgroups of autistic patients may be marked by intermediate phenotypes, such as elevated serotonin (5-HT) blood levels, potentially associated with different underlying disease mechanisms. This could lead to inconsistent genetic association results, such as those of prior studies on serotonin transporter (5-HTT) gene promoter variants and autistic disorder. Contributions of 5-HTT gene promoter alleles to 5-HT blood levels were thus investigated in 134 autistic patients and 291 first-degree relatives. Mean 5-HT blood levels are 11% higher in autistic patients carrying the L/L genotype, compared to patients with the S/S or S/L genotype; this trend is not observed in first-degree relatives. The probability of inheriting L or S alleles is significantly enhanced in patients with 5-HT blood levels above or below the mean, respectively (P Ͻ 0.05), but quantitative TDT analyses yield a non-significant trend (P = 0.10), as this polymorphism explains only 2.5% of the variance in 5-HT blood levels of autistic patients. In conclusion, 5-HTT gene promoter variants seemingly exert a small effect on 5-HT blood levels in autistic children, which largely does not account for hyperserotoninemia. Nonetheless, the inconsistent outcome of prior association studies could partly stem from a selection bias of hyper-or hypo-serotoninemic probands.

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

“…These findings are in accordance with functional effects on higher platelet serotonin uptake mediated by the long allele variants of 5HTTLPR in healthy controls. 229 No difference was found between genotypes for whole-blood serotonin levels in two samples of individuals with AD, 236,245 which parallels the findings in healthy controls.…”

Autism genetics: Methodological issues and experimental design

“…Another vulnerability gene, MET, was identified by Campbell and Levitt collaborating with our group for the genetic studies involved in this project [80,81]. In addition, we have identified other new vulnerability genes and confirmed associations initially reported in other samples for several genes, including ADA [82], APOE [83], HOXA1 [84,85], ITG-B3 [86], PON1 [87], PRKCB1 [88], SLC6A4 [89,90], SLC-25A12 [91].…”

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

“…6,10,36 Performing a quantitative TDT, as implemented by the FBAT program, 38 we found a significant association between parent-to-autistic offspring transmission rates of PRKCB1 gene variants marked by the two most 5 0 SNPs, rs3785392 and rs3785387, and urinary peptide excretion rates (Table 5and Supplementary Table S3 Table S4). Incorporating peptiduria as a covariate into haplotypic and single-marker analyses for affection status essentially did not change their outcome: the whole marker permutation test for haplotypic analysis yielded a P = 0.054, while single-marker analyses for rs3785392 and rs3785387 yielded P = 0.02 and 0.11, respectively (compare with Tables 4A and 4B).…”

“…36 Urinary peptide excretion analysis was performed by high-performance liquid chromatography on the first morning from urine samples of all family members, diluted to 250 nm creatinine, as described. 10 The total area of peaks under the 215 nm absorption curve in the peptide region following the hippuric acid peak was calculated and expressed in mm 2 .…”

“…40 To minimize the impact of confounding variables, such as drug therapy, puberal status and differential growth rates, quantitative analyses were restricted to patients aged < 11 years and not taking selective 5-HT reuptake inhibitors for 5-HT blood levels, and to patients aged < 16 years for head size, as in our previous studies. 6,33,36 Statistical analyses were performed merging together our 210 Italian and 24 CaucasianAmerican families (Table 1) after population structure analyses provided no evidence of major genetic dyshomogeneity in a subset of 155 Italian and 24 Caucasian-American patients randomly chosen one per family, genotyped at 90 unlinked SNPs distributed genome-wide and analyzed using the Structure program, as described (see Supplementary Methods). 41 Data are expressed as mean ± s.e.m., except for head circumference and urinary peptide excretion rates, expressed as median percentile±interquartilic range.…”