Is a Functional Serotonin Transporter Polymorphism Linked to the Core Symptoms of Autism or Comorbid Psychopathology?

Background: The serotonin transporter strongly modulates serotonin function and is a major pharmacological target in the treatment of repetitive behaviour in autism as well as in the treatment of comorbid anxiety and depression. The 5-HTTLPR variant in the Serotonin Transporter Gene has been repeatedly assessed for association with autism leading to contradictory results. Recently, the functional SNP rs25531 (A/G) within the long allele (L) was described. The A variant of SNP rs25531 within the long allele (L_A) leads to higher expression, the dominant short allele (S_A, S_G) and L_G lead to lower expression of the serotonin transporter.

Objectives: We hypothesize that (1) The L_A allele of the serotonin transporter polymorphism, HTTLPR, alters the risk of autism and (2) the L_AL_A genotype is linked to autistic symptoms (especially repetitive behavior) and to comorbid psychopathology like anxiety, OCD and depression. Methods: (1) We performed genotyping in a German trio sample of 248 patients with autism and their parents. The transmission of the long and short alleles of the HTTLPR polymorphism including the rs25531 was investigated using the transmission disequilibrium test (TDT). (2) Additional linear regression analyses were performed to explore the influence of the L_AL_A genotype on behavioral characteristics measured by the Autism Diagnostic Interview-Revised and the Child Behavior Checklist.

Results: A trend towards higher transmission of the L_A allele of HTTLPR/rs25531 was found in the sample of autistic patients (nominal p value= .047). Within the subgroup of patients with the L_AL_A genotype (n=75) repetitive behavior was slightly increased but this difference did not reach significance (p= .13). No association with other core features of autism such as communication deficits or deficits in social interaction was observed.

Conclusions: The results indicate that the L_A allele of HTTLPR/rs25531 may play a role in the pathogenesis of autism, but – contradictory to  results of previous studies - seems not to influence phenotypic variability within autism.