Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism

Jilly Naaijen ,Richard Anney,Michael Gill,Herbert Roeyers,Philip Asherson,Fernando Mulas,Hans-Christoph Steinhausen,Tobias Banaschewski,Aribert Rothenberger,Ana Miranda,Joseph A Sergeant ,Barbara Franke,Stephen V Faraone ,Jan K Buitelaar ,Edmund Sonuga‐Barke ,Robert D Oades ,Janita Bralten ,Jeffrey Glennon ,Richard P Ebstein ,Geert Poelmans

doi:10.1038/tp.2016.273

Abstract

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.

Highlights

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by ageinappropriate inattentiveness and/or increased hyperactivity and impulsivity.[1]
Moderate correlations were found between the two symptom domains of ADHD (0.506, P o 0.01) and weak correlations were found between hyperactivity/impulsivity symptom severity and autism symptom severity (0.077, P o 0.05)
Symptoms coexist across ADHD and autism spectrum disorder (ASD), only weak correlations were found between hyperactivity/impulsivity symptom severity and ASD symptoms, and no correlations were found between inattention and ASD symptoms

Summary

INTRODUCTION

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by ageinappropriate inattentiveness and/or increased hyperactivity and impulsivity.[1]. Genome-wide genotyping of the IMAGE probands was performed as part of the Genetics Association Information Network study using the Perlegen genotyping platform, described previously.[56] An imputation approach was used with the Hapmap II release 22 data set.[57] The imputed data underwent quality control, in which SNPs with an imputation score lower than 0.5 and minor allele frequency lower than 0.01 were excluded After this step, 2 182 904 SNPs across the genome were retained, excluding the account the heterogeneity of the disorders as well as the extent of overlap between them.[14,47] Complementary, because of the common deficit of inhibitory control in ADHD and ASD and because of its regulation by frontostriatal glutamatergic and GABAergic signaling, we investigated in a subsample whether the genes for glutamate and GABA neurotransmission are involved in inhibitory control.

RESULTS

DISCUSSION

CONFLICT OF INTEREST