Family‐Based Clinical Associations and Functional Characterization of the Serotonin 2AReceptor Gene (HTR2A) in Autism Spectrum Disorder

Abstract

The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor “A” allele of rs6311 to offspring with ASD (permuted p=0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5′ untranslated region in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5′UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk.

Testing Genetic Modifiers of Behavior and Response to Atomoxetine in Autism Spectrum Disorder with ADHD

“…Families were recruited as previously reported (Cottrell et al, 2011; Smith et al, 2014). Caucasian participants with ADI-R scores and genetic material were used for the current analyses (74 boys, 14 girls, N=88).…”

“…Genomic DNA was isolated and SNPs genotyped as previously reported (Smith et al, 2014). Briefly, genomic DNA was extracted from either whole blood or saliva.…”

“…These SNPs have demonstrated an effect at the mRNA level in previous work and they have been associated with mental health disorders in at least one other study (Lim et al, 2007; Zhang et al, 2007; Retz et al, 2008; Moyer et al, 2011; Pinsonneault et al, 2011; Bray et al,. 2013; Barrie et al, 2014; Smith et al, 2014). …”

Bio-collections in autism research

“…Low levels of RORA causes dysregulation of these genes and associated pathways. Prefrontal cortex and cerebellum tissue was used.[350]ATPBrain tissue (ATP)153 families (other)54 subjects (ATP)Functional characterisation studyVariant of the HTR2A gene rs6311 in ASD patients has lower level of expression and contains extended 5′untranslated region. Speculation that this variant could be a risk factor in ASD.…”

Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders

“…Case-control studies involving −1438 A/G polymorphism have demonstrated overrepresentation of G allele in the autistic than in the control group (Abdelrahman et al, 2014;Hranilovic et al, 2010). Family based study conducted by Smith et al (2014) also suggested significant under-transmission of minor A allele to offspring with ASD. A previous study by the same group showed that −1438 A allele decreased the expression of HTR2A mRNA with an extended 5 untranslated region (UTR) in the frontopolar cortex of the brain (Smith et al, 2013).…”