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

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.

Figure 1. Altered K_m and V_max by SLC6A4 diplotype group

Mean values with standard error of the mean of [¹⁴C]-5-HT binding affinity K_m (A) and [¹⁴C]-5-HT uptake V_max (B) are shown for each of three SLC6A4 diplotype groups. Subjects in the TT/TT group had two haplotypes (i.e., a diplotype) containing the SNP10-SNP11 T-T haplotype. All of these subjects had HTTLPR S/S or S/L genotypes. Subjects in the L/L group had two haplotypes containing the HTTLPR L allele. Subjects in the ‘Other’ group had other combinations of haplotypes and all had HTTLPR S/S or S/L genotypes.

Figure 2. Altered whole blood 5-HT by TPH1 diplotype group

Mean values with standard error of the mean of whole blood 5-HT are shown for subjects with three different TPH1 diplotypes, containing either none, one, or two copies of the rs1799913-rs623580 haplotype.