Variation in glutamate and GABA genes and their association with brain structure and chemistry in autism

The excitatory/inhibitory (E/I) imbalance hypothesis posits that an imbalance between glutamatergic and GABAergic neurotransmission contributes to autism symptomatology. Whether this is due to altered GABAergic or glutamatergic functioning, or both, remains largely unknown. We integrated genetic, brain structure and brain chemistry data to investigate the relationship between E/I genetic variation and expression, glutamate concentrations and cortical thickness (CT). Participants (60 autism and 104 neurotypical controls, aged 8-13 years) underwent magnetic resonance imaging and spectroscopy for glutamate quantification in the anterior cingulate cortex (ACC) and left dorsal striatum. Genetic involvement in these regional glutamate concentration levels was investigated using competitive gene-set association and polygenic scores (PGS). Further, glutamate as well as GABA gene-set expression profiles were investigated in relation to CT. Aggregated genetic variation in the glutamate gene-set was associated with ACC but not striatal glutamate concentrations. PGS analysis, however, showed a genome-wide PGS for autism to be predictive of striatal but not ACC glutamate levels. Expression profiles of GABAergic-but not glutamatergic genes were associated with differences in cortical thickness between groups. This study showed differential involvement of aggregated glutamatergic and GABAergic genetic variation in brain structure and chemistry in autism, which suggests regional variability in E/I imbalance. ### Competing Interest Statement D Brandeis serves as an unpaid scientific advisor for an EU-funded Neurofeedback trial unrelated to the present work. DJ Lythgoe has acted as a consultant for Ixico PLC. JK Buitelaar has been consultant to/member of advisory board of and/or speaker for Janssen Cilag BV, Eli Lilly, Shire, Roche, Angelini, and Servier. He is not an employee of any of these companies, nor a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. G Poelmans is director of Drug Target ID, Ltd. The remaining authors declare no conflict of interest. The present work is unrelated to the grants and relationships noted earlier.