title: Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism.
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.
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute of Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Naaijen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Bralten
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Poelmans
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute of Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Glennon
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.|Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute of Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands.
authors.forename: J K
authors.initials: JK
authors.lastname: Buitelaar
mesh_terms: D000293:Adolescent; D027241:Amino Acid Transport System y+L; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D002135:Calcium-Binding Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D027301:Fusion Regulatory Protein 1, Light Chains; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D012720:Severity of Illness Index; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D027241:Amino Acid Transport System y+L; D002135:Calcium-Binding Proteins; D027301:Fusion Regulatory Protein 1, Light Chains; D018698:Glutamic Acid; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; C408467:CALML5 protein, human; C546257:GABRA3 protein, human; C546274:GABRE protein, human; C561870:GABRQ protein, human; C485668:GRIN1 protein, human; C421261:SLC7A7 protein, human; C104723:glutamate receptor ionotropic, AMPA 3; C108822:metabotropic glutamate receptor 2