Estimating differing causal roles of glutamate and GABA genes on brain and behavior in autism

Abstract The excitatory/inhibitory (E/I) imbalance theory suggests that excitatory and inhibitory alterations underlies autism characteristics. However, genetic underpinnings of this imbalance and its impact on brain function and behavior remains unclear. We explored causal links between glutamate and GABA gene-set polygenic scores (PGS) for autism and core autism characteristics, putting particular attention on the restricted- and repetitive behaviors (RRBs) domain by including functional activity (fMRI) during inhibitory control (in the anterior cingulate cortex (ACC) and striatum). Causal links between genes, brain and behavior was evaluated using Bayesian Constraint-based Causal Discovery (BCCD) algorithms, to build causal models of these relationships in a discovery sample (LEAP cohort: autistic = 343, neurotypical = 253) and two generalization cohorts with partially overlapping measures (TACTICS cohort: autistic = 60, neurotypical = 100, Simon Simplex Collection: autistic = 2756). In the discovery sample, we found a causal link between glutamate PGS and core clinical characteristics of autism, particularly the communication domain (Autism Diagnostic Interview-Revised) in autistic participants, with 95% reliability. We did not find links between functional activity during inhibitory control and other measures. For one generalization cohort, we further report on the impact of 1 H-MRS measures of glutamate, identifying a causal link between GABA autism PGS on ACC glutamate concentrations. Not all links were identified in the generalization cohorts, which may be due to clinical and genetic differences between the cohorts. While our results reinforce the previously found association between glutamate genes and core clinical autism behaviors, task-based functional activity may not be causally related to RRBs.