Common Polymorphisms in GABRB3 Are Associated with Asperger Syndrome and Related Endophenotypes

Background: Autism Spectrum Conditions (ASC) are neurodevelopmental and are associated with deficits in social interaction and communication alongside unusually repetitive, restricted, and stereotyped behaviour. Within the spectrum there is considerable variability in both cognitive and behavioural endophenotypes. Asperger Syndrome (AS) is a subset of ASC where the development of language and intelligence is preserved. Genetic association and expression studies have consistently implicated the GABA-ergic system in ASC. GABRB3 encodes a key component of the GABA-ergic system and has been previously associated with ASC and normative variation in empathy and sensory sensitivity. Few genetic studies have focused specifically on AS.

Objectives: To conduct a candidate gene association study of common polymorphisms in GABRB3 for AS and six other related endophenotypes.

Methods: 45 single nucleotide polymorphisms (SNPs) were tested for association with AS in a cohort of n = 530 individuals (412 controls: 185 males, 227 females; 118 cases: 74 males, 44 females).  Additionally, we also tested the 45 SNPs for association with six related quantitative traits measured in controls through the following tests: the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ), the Systemizing Quotient-Revised (SQ-R), the Embedded Figures Test (EFT), the Reading the Mind in the Eyes Test (RMET), and the Mental Rotation Test (MRT). Allelic and two-loci SNP-SNP interaction tests were performed for both case-control and quantitative traits. Additionally 2-loci, 3-loci, 4-loci and one 7-loci haplotype analyses were performed in the AS case-control sample. All analyses were performed using Plink version 1.07. Correction for multiple testing for allelic association and SNP-SNP interaction tests were performed using Bonferroni correction, after accounting for LD between the SNPs investigated. Haplotype analyses were corrected using permutation correction.

Results: Three individual SNPs (rs7180158, rs7165604, rs12593579) were significantly associated with a clinical diagnosis of AS. Using haplotype analysis, we identified a 19kb genomic region (rs7180158-rs7174437; Chr15:26978238 - 26997923) that formed an LD block, which was significantly associated with AS. This genomic region encompasses all three significantly associated SNPs with AS and is less than 10kb downstream from 155CA-2, a microsatellite marker that was previously associated with ASC.

Two SNPs (rs9806546, rs11636966) were significantly associated with EQ in controls. We did not identify any allelic associations with the remaining quantitative endophenotypes tested. Two SNP-SNP pairs – rs12438141-rs1035751, rs12438141-rs7179514 – showed significant interaction in association with the EFT in controls. One SNP-SNP pair – rs7174437-rs1863455 – was significantly associated with the MRT in controls.  

Conclusions: This is the first study to specifically test this number of common SNPs in GABRB3 with AS, and with a comprehensive set of endophenotypes. The current study confirms the role of GABRB3 as an important candidate gene in both ASC and normative variation in related endophenotypes.