Genetic variant rs17225178 in the ARNT2 gene is associated with Asperger Syndrome.

Agnese Di Napoli,Bhismadev Chakrabarti,Simon Baron-Cohen,Varun Warrier

doi:10.1186/s13229-015-0009-0

Abstract

BackgroundAutism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Asperger Syndrome (AS) is one subgroup of ASC and differs from classic autism in that in AS there is no language or general cognitive delay. Genetic, epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. A mutation in this gene has been identified in individuals with ASC and single nucleotide polymorphisms (SNPs) have been nominally associated with AS and autistic traits in previous studies.MethodsIn this study, we tested 34 SNPs in ARNT2 for association with AS in 118 cases and 412 controls of Caucasian origin. P values were adjusted for multiple comparisons, and linkage disequilibrium (LD) among the SNPs analysed was calculated in our sample. Finally, SNP annotation allowed functional and structural analyses of the genetic variants in ARNT2. We tested the replicability of our result using the genome-wide association studies (GWAS) database of the Psychiatric Genomics Consortium (PGC).ResultsWe report statistically significant association of rs17225178 with AS. This SNP modifies transcription factor binding sites and regions that regulate the chromatin state in neural cell lines. It is also included in a LD block in our sample, alongside other genetic variants that alter chromatin regulatory regions in neural cells.ConclusionsThese findings demonstrate that rs17225178 in the ARNT2 gene is associated with AS and support previous studies that pointed out an involvement of this gene in the predisposition to ASC.

Highlights

Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests
Our study provides further support for a role of aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) in ASC and in particular it points out an involvement of a single nucleotide polymorphism (SNP) in the predisposition to Asperger Syndrome (AS)
Recent studies have reported a mutation in the ARNT2 gene in ASC [26] and common variants associated with autistic traits [28]

Summary

Introduction

Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. Autism Spectrum Conditions (ASC) are a group of neurodevelopmental conditions defined by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Male:female sex ratios of 9:1 and 4:1 are observed in ASC are neurodevelopmental in origin, and genes involved in neural development and connectivity are good candidate genes for studying the genetics of these conditions [10,11].

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