Network oriented variant analysis of the serotonin transporter regulome

Background: Autism has a predominantly genetic etiology but one characterized by substantial heterogeneity. Heritable hyperserotonemia in ~30% of cases points to dysregulation of serotonin being an important clue to genetic liability in autism. We have described rare serotonin transporter (SERT) coding variants that confer a gain-of-function and are associated with autism and related disorders showing rigid-compulsive behaviors. Objectives: We hypothesize that loci encoding molecules regulating SERT harbor alleles conferring risk for autism. We examined loci for the A3 adenosine receptor (ADORA3), 5-HT1B receptor (HTR1B), neuronal nitiric oxide synthase (NOS1), and syntaxin 1A (STX1A) for evidence of autism related alleles. Methods: To test for allelic associations, tag SNPs representing common haplotypes (>5%) and coding polymorphisms were genotyped in a sample of 940 autism families. Preliminary resequencing analysis was performed using a panel of unrelated autism probands to identify novel variants in transcribed and potential regulatory regions. Results: Preliminary association studies suggest that common alleles at the ADORA3 and HTR1B loci are not significantly associated with autism. One marker (rs9654749) within STX1A shows nominally significant association. NOVA has identified several synonymous and nonsynonymous variants in these SERT regulome genes ADORA3 and NOS1. While control sequencing is ongoing, genotype analysis of one ADORA3 and two NOS1 novel coding variants suggests that they are not disease-related. Conclusions: Despite the absence of strong association or disease-causing variants in these initial studies, further examination of the SERT regulatory network hypothesis is warranted. Additional allelic association and resequencing studies including controls where appropriate are ongoing to address disease susceptibility within these genes.