Genes related to sex steroids, neural growth, and social–emotional behavior are associated with autistic traits, empathy, and Asperger syndrome

Abstract

Genetic studies of autism spectrum conditions (ASC) have mostly focused on the "low functioning" severe clinical subgroup, treating it as a rare disorder. However, ASC is now thought to be relatively common ( approximately 1%), and representing one end of a quasi-normal distribution of autistic traits in the general population. Here we report a study of common genetic variation in candidate genes associated with autistic traits and Asperger syndrome (AS). We tested single nucleotide polymorphisms in 68 candidate genes in three functional groups (sex steroid synthesis/transport, neural connectivity, and social-emotional responsivity) in two experiments. These were (a) an association study of relevant behavioral traits (the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ)) in a population sample (n=349); and (b) a case-control association study on a sample of people with AS, a "high-functioning" subgroup of ASC (n=174). 27 genes showed a nominally significant association with autistic traits and/or ASC diagnosis. Of these, 19 genes showed nominally significant association with AQ/EQ. In the sex steroid group, this included ESR2 and CYP11B1. In the neural connectivity group, this included HOXA1, NTRK1, and NLGN4X. In the socio-responsivity behavior group, this included MAOB, AVPR1B, and WFS1. Fourteen genes showed nominally significant association with AS. In the sex steroid group, this included CYP17A1 and CYP19A1. In the socio-emotional behavior group, this included OXT. Six genes were nominally associated in both experiments, providing a partial replication. Eleven genes survived family wise error rate (FWER) correction using permutations across both experiments, which is greater than would be expected by chance. CYP11B1 and NTRK1 emerged as significantly associated genes in both experiments, after FWER correction (P<0.05). This is the first candidate-gene association study of AS and of autistic traits. The most promising candidate genes require independent replication and fine mapping.

Associations between oxytocin-related genes and autistic-like traits

“…In previous studies, Chakrabarti et al found an association between rs2770378 and ASD diagnosis (Chakrabarti et al, 2009), while Yrigollen et al, in contrast with our results, found no association with ASD on a number of assessment scales (Yrigollen et al, 2008). Neither of these studies performed sex-specific analyses.…”

“…Interestingly, SNPs in the human ARNT2 gene have been associated with ASD (Chakrabarti et al, 2009). …”

Endocannabinoid Signaling in Autism

“…Another study in an independent sample used eyegaze tracking to show that the same CNR1 polymorphisms were associated with greater gaze duration to happy faces, but again not to disgust faces [118]. A parallel population genetic study found a nominal association of the same CNR1 genetic variations with trait empathy [119]. Individuals with ASD score low in trait empathy, and, consistent with this, a gene expression study in postmortem brains of individuals with autism had earlier reported a reduced expression of CB 1 [120,121].…”

Asymmetry within and around the human planum temporale is sexually dimorphic and influenced by genes involved in steroid hormone receptor activity

“…We also created one additional, custom gene set that comprised the genes listed by (Chakrabarti et al, 2009). This was a manually created gene set containing key genes involved in androgen and estrogen biology.…”