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

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

doi:10.1038/tp.2016.273

Cited by 112 publications

(97 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Additionally, a direct and functional interaction between PICK1 and dopamine D 3 receptors (D 3 R) has been reported [57]. Furthermore, PICK1 has a role in glutamate receptor regulation [58], and a recent study revealed that a glutamate gene-set showed association with the severity of hyperactivity/impulsivity in an ADHD case-only sample [59]. In addition, adult Pick1 knockout mice show several behavioral abnormalities, such as hyperactivity and electrophysiological deficits in the prefrontal cortex [60].…”

Section: Discussionmentioning

confidence: 99%

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

et al. 2018

View full text Add to dashboard Cite

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N total = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A more recent analysis reported overrepresentation of glutamatergic GO in ADHD cases . A study that looked at both CNV as well as SNP in samples from five pooled ADHD studies in comparison to data from autism and schizophrenia found six enriched pathways that included plausible ones, such as ‘ligand‐gated ion channel activity,’ and more opaque ones, such as ‘respiratory electron transport.’ There was huge overlap between schizophrenia, autism, and ADHD.…”

Section: Molecular Genetic Studiesmentioning

confidence: 99%

Recent developments in the genetics of attention‐deficit hyperactivity disorder

Grimm

Kittel‐Schneider

Reif

2018

Psychiatry Clin Neurosci

View full text Add to dashboard Cite

Attention-deficit hyperactivity disorder (ADHD) is a developmental psychiatric disorder that affects children and adults. ADHD is one of the psychiatric disorders with the strongest genetic basis according to familial, twin, and single nucleotide polymorphisms (SNP)-based epidemiological studies. In this review, we provide an update of recent insights into the genetic basis of ADHD. We discuss recent progress from genome-wide association studies (GWAS) looking at common variants as well as rare copy number variations. New analysis of gene groups, so-called functional ontologies, provide some insight into the gene networks afflicted, pointing to the role of neurodevelopmentally expressed gene networks. Bioinformatic methods, such as functional enrichment analysis and protein-protein network analysis, are used to highlight biological processes of likely relevance to the etiology of ADHD. Additionally, copy number variations seem to map on important pathways implicated in synaptic signaling and neurodevelopment. While some candidate gene associations of, for example, neurotransmitter receptors and signaling, have been replicated, they do not seem to explain significant variance in recent GWAS. We discuss insights from recent case-control SNP-GWAS that have presented the first whole-genome significant SNP in ADHD.

show abstract

“…Reduced concentration of extracellular GABA has been detected in children with ADHD, therefore abnormal functioning GABAergic cells may be relevant to ADHD (43). Furthermore, a genetic association was uncovered between GABAergic genes and ADHD symptoms (Naaijen et al, 2017). These data suggest that the role of these cell types in ADHD should be further studied.…”

Section: Discussionmentioning

confidence: 99%

Spatial organization of cells and variable expression of autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in Attention-Deficit/Hyperactivity Disorder

Hess

Radonjić

Patak

et al. 2019

Preprint

View full text Add to dashboard Cite

Genetically influenced changes in brain organization occur over the course of development. Large-scale brain imaging studies by the ENIGMA Consortium identified structural changes associated with attention-deficit/hyperactivity disorder (ADHD). It is not clear why some brain regions are impaired and others spared by the etiological risks for ADHD. We hypothesized that spatial variation in brain cell organization and/or pathway expression levels contribute to selective brain region vulnerability (SBRV) in ADHD. In this study, we used the largest available collection of imaging results from the ADHD ENIGMA Consortium along with high-resolution postmortem brain microarray data from Allen Brain Atlas from 22 sub-cortical and cortical brain regions to investigate our selective brain region vulnerability (SBRV) hypothesis. We performed deconvolution of the bulk transcriptomic data to determine abundances of neuronal and non-neuronal cells in the brain. We then assessed the relationships between gene set expression levels, cell abundance, and standardized effect sizes representing regional changes in brain sizes in cases of ADHD. Our analysis yielded significant correlations between apoptosis, autophagy, and neurodevelopment genes with reductions in regional brain sizes in ADHD, along with associations to regional abundances of dopaminergic neurons, astrocytes, oligodendrocytes, and neural progenitor cells. This works provides novel mechanistic insights into SBRV in ADHD.

show abstract

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

Cited by 112 publications

References 71 publications

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

Recent developments in the genetics of attention‐deficit hyperactivity disorder

Spatial organization of cells and variable expression of autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in Attention-Deficit/Hyperactivity Disorder

Contact Info

Product

Resources

About