Association of rs2129575 in the tryptophan hydroxylase 2 gene with clinical phenotypes of autism spectrum disorders


SEROTONIN HAS BEEN shown to be involved in neurobiological mechanisms that underlie autism spectrum disorders (ASD).[1] The gene that encodes tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in serotonin synthesis in the brain, is a promising gene for ASD. Recently, we reported an association between rs2129575 of TPH2 and ASD in a Japanese population.[2] This polymorphism has also been associated with ASD and clinical symptoms of ASD in a Korean population.[3] Here, we assessed the effects of rs2129575 on clinical phenotypes of ASD.

The present study was approved by the Ethics Committee on Genetics of the Niigata University School of Medicine, and written informed consent was obtained from all participants and/or their families. To evaluate the effects of rs2129575 on subdivided clinical phenotypes of ASD, we used a case-only study design. The study involved 110 Japanese ASD individuals (82 were male and 28 were female; mean age, 14.9 [SD 7.6]; mean full-scale intelligence quotient [IQ], 92.2 [SD 14.4]). They were diagnosed according to the DSM-IV criteria. The autistic symptoms of all participants were assessed using the Childhood Autistic Rating Scale-Tokyo Version (CARS-TV).[4] The CARS-TV consists of 15 items on a four-point scale (1, behavior appropriate for age; 2, mildly abnormal; 3, moderately abnormal; and 4, severely abnormal) with three midpoints. We genotyped rs2129575 using the TaqMan 5′-exonuclease assay.[2] We compared mean CARS-TV item scores between G allele homozygotes and T allele carriers using ancova with full-scale IQ as the covariates. The two groups were matched for sex, age and full-scale IQ (Table S1). We used the Benjamini–Hochberg procedures to control the false discovery rate at 0.05.

The mean score for the Body Use item was significantly lower in the major G allele homozygotes of rs2129575 than in the T allele carriers (1.5 ± 0.6 and 2.0 ± 0.6, respectively, corrected P = 0.015; Table S1).

The G allele of rs2129575 is associated with relatively mild clinical symptoms of ASD individuals in our Japanese population and Korean population.[3] Notably, the G allele homozygotes have been reported to have higher serotonin synthesis in the orbitofrontal cortex than the T allele carriers.[5] These findings suggest that rs2129575 may cause some kind of dysfunction in the serotonergic system underlying clinical phenotypes of ASD.