Variation in the autism candidate gene GABRB3 modulates tactile sensitivity in typically developing children

Abstract

BackgroundAutism spectrum conditions have a strong genetic component. Atypical sensory sensitivities are one of the core but neglected features of autism spectrum conditions. GABRB3 is a well-characterised candidate gene for autism spectrum conditions. In mice, heterozygous Gabrb3 deletion is associated with increased tactile sensitivity. However, no study has examined if tactile sensitivity is associated with GABRB3 genetic variation in humans. To test this, we conducted two pilot genetic association studies in the general population, analysing two phenotypic measures of tactile sensitivity (a parent-report and a behavioural measure) for association with 43 SNPs in GABRB3.FindingsAcross both tactile sensitivity measures, three SNPs (rs11636966, rs8023959 and rs2162241) were nominally associated with both phenotypes, providing a measure of internal validation. Parent-report scores were nominally associated with six SNPs (P <0.05). Behaviourally measured tactile sensitivity was nominally associated with 10 SNPs (three after Bonferroni correction).ConclusionsThis is the first human study to show an association between GABRB3 variation and tactile sensitivity. This provides support for the evidence from animal models implicating the role of GABRB3 variation in the atypical sensory sensitivity in autism spectrum conditions. Future research is underway to directly test this association in cases of autism spectrum conditions.

Reply to Dickinson and Milne

“…Although there are always counter examples to be found, our results are consistent with numerous findings of GABAergic impairments in autism: sensorimotor GABA has been shown to be altered in children with ASD (Gaetz et al 2013); short intercortical inhibition, a metric of inhibition measured by transcranial magnetic stimulation, is impaired in ASD (Enticott et al 2013); and numerous GABAergic genes have been linked to ASD (Abrahams and Geschwind 2008;Buxbaum et al 2002;DeLorey 2005). Some of these metrics have also been linked to task performance: detection threshold has been linked to expression of the GABRB3 gene (Tavassoli et al 2012); our own work has shown GABA levels predict tactile frequency discrimination (Puts et al 2011). …”

Increased Sensory Processing Atypicalities in Parents of Multiplex ASD Families Versus Typically Developing and Simplex ASD Families

“…Given that this study used online questionnaires to understand traits contributing to ASD genetic liability, evident next steps also include genetic association studies to discover the genes underpinning our results, similar to the pilot study by Tavassoli et al (2012). …”

“…Based on past research demonstrating that sensory processing abnormalities are heritable (Goldsmith et al 2006) and related to ASD candidate genes (DeLorey et al 2011; Peñagarikano et al 2011; Tavassoli et al 2012), it was hypothesized that parents of ASD children who presumably have the highest genetic liability for ASD (MPX) would differ from parents with lower ASD genetic liability (SPX) and parents with no such liability (parents of typically developing children; P - TD) in sensory processing scores on all four quadrants of the AASP.…”

Tactile hypersensitivity and GABA concentration in the sensorimotor cortex of adults with autism

“…Genetic results also suggest a link between tactile sensitivity and GABA. Indeed, genetic variations in the GABRB3 gene (an autism candidate gene encoding a subunit of GABA A receptors) have been associated with modulations of tactile sensitivity in the human general population [Tavassoli, Auyeung, Murphy, Baron-Cohen, & Chakrabarti, 2012], as well as in a mouse model of ASD [DeLorey et al, 2011;Orefice et al, 2016].…”