A possible influence of the GAD2 gene on cortical brain volume in Autistic Spectrum Disorders

Background: The GABAergic system has emerged as a candidate neurotransmitter system underpinning the pathophysiology of Autistic Spectrum Disorders (ASD). Glutamic Acid Decarboxylase (GAD) is a crucial enzyme responsible for the decarboxylation of glutamate to gamma-amino butyric acid. Two isoformes of this enzyme are present GAD1 and GAD2; two different genes found on chromosome 2 and 10 respectively encode these. Linkage analysis have identified chromosome 10 as having high association with ASD and a recent SNP association analysis within our group found a significant association with GAD2 and ASD. Post-mortem analyses have shown a reduced GAD protein levels in autistic parietal and cerebellar cortices. However nobody has related genetic variation in GAD to brain.

Objectives: To investigate the association between the GAD2 gene and cortical anatomy in ASD.

Methods: A sample of 64 individuals (42 clinically diagnosed ASD cases and 22 healthy controls) underwent a conventional SPGR scan; FreeSurfer software was used to automatically label 34 subdivisions of each hemisphere and calculate cortical volumes. Each subject was genotyped for 10 SNPs tagging the GAD2 gene using Taqman procedures. Haplo.Stats was used in conjunction with R Statistically Computing for haplotypic and statistical analysis.

Results: We found a significant decrease in cortical volume of ASD inferior parietal cortex (p = 0.0089). Haplo.Stats identified a significantly associated 3 marker haplotype with ASD cases. All possible haplotype combinations were identified and their frequencies calculated. Hap1 and Hap3 showed the highest frequencies and were examined further. Subjects expressing Hap3 showed a significant increase in inferior parietal cortical volume (0.00025), however a significant reduction was noted in ASD cases expressing Hap3 (0.0005) using generalized linear regression analysis.

Conclusions: Our work adds to post mortem evidence that Cortical volume reduction in the left inferior parietal cortex of the ASD brain may be related to haplotypes of the GAD2 gene.