From Rare Copy Number Variants to Biological Processes in ADHD

Harich, Benjamin; Voet, Monique van der; Klein, Marieke; Cizek, Pavel; Fencková, Michaela; Schenck, Annette; Franke, Barbara

doi:10.1176/appi.ajp.2020.19090923

Cited by 35 publications

(27 citation statements)

References 86 publications

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“…In a large meta-analysis of seven genome-wide linkage scans in search of loci associated with ADHD, it was determined that the chr16q23.1-qter region, precisely the genomic region containing WWOX, had a very highly significant risk association with ADHD [48]. Furthermore, Harich et al, using data from CNV studies from 6176 ADHD individuals and using multiple additional bioinformatic approaches, identified WWOX as one of a relatively small set of 26 candidate ADHD genes [49]. Distribution of WWOX locus CNVs associated with ASD and ID cases obtained from the AutDB database (http://www.mindspec.org/autdb.html).…”

Section: Figure 8 Wwox Germline Copy Number Variants (Cnvs) In Autism Spectrum Disorder (Asd)mentioning

confidence: 99%

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

Aldaz

Hussain

2020

IJMS

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The WWOX gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. WWOX biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early infantile epileptic encephalopathy (EIEE28; MIM:616211). WWOX germline copy number variants have also been associated with autism spectrum disorder (ASD). All identified germline genomic variants lead to partial or complete loss of WWOX function. Importantly, large-scale genome-wide association studies have also identified WWOX as a risk gene for common neurodegenerative conditions such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Thus, the spectrum of CNS disorders associated with WWOX is broad and heterogeneous, and there is little understanding of potential mechanisms at play. Exploration of gene expression databases indicates that WWOX expression is comparatively higher in the human cerebellar cortex than in other CNS structures. However, RNA in-situ hybridization data from the Allen Mouse Brain Atlas show that specific regions of the basolateral amygdala (BLA), the medial entorhinal cortex (EC), and deep layers of the isocortex can be singled out as brain regions with specific higher levels of Wwox expression. These observations are in close agreement with single-cell RNA-seq data which indicate that neurons from the medial entorhinal cortex, Layer 5 from the frontal cortex as well as GABAergic basket cells and granule cells from cerebellar cortex are the specific neuronal subtypes that display the highest Wwox expression levels. Importantly, the brain regions and cell types in which WWOX is most abundantly expressed, such as the EC and BLA, are intimately linked to pathologies and syndromic conditions in turn associated with this gene, such as epilepsy, intellectual disability, ASD, and AD. Higher Wwox expression in interneurons and granule cells from cerebellum points to a direct link to the described cerebellar ataxia in cases of WWOX loss of function. We now know that total or partial impairment of WWOX function results in a wide and heterogeneous variety of neurodegenerative conditions for which the specific molecular mechanisms remain to be deciphered. Nevertheless, these observations indicate an important functional role for WWOX in normal development and function of the CNS. Evidence also indicates that disruption of WWOX expression at the gene or protein level in CNS has significant deleterious consequences.

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Section: Figure 8 Wwox Germline Copy Number Variants (Cnvs) In Autism Spectrum Disorder (Asd)mentioning

confidence: 99%

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

Aldaz

Hussain

2020

IJMS

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“…A recent genome-wide meta-analyses identified shared risk loci for ADHD and intelligence [31]. Rare genetic variants have also been identified for cognition [75,76] and ADHD [77], with overlapping genes implicated in ADHD studies of common and rare variants [78]. However, while there is evidence of common and rare variants disrupting similar biological pathways in ADHD [79], the neurobiological mechanisms underlying shared genetic influences on ADHD and intelligence remain unclear [31].…”

Section: Discussionmentioning

confidence: 99%

Genetic influences on externalizing psychopathology overlap with cognitive functioning and show developmental variation

et al. 2021

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Background Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation. Methods Using data from 9,421 individuals aged 8 to 21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation. ResultsExternalizing was heritable (h 2 =0.46, p=1x10 -6 ), but not anxious-misery (h 2 =0.09, p=0.183), fear (h 2 =0.04, p=0.337), psychosis-spectrum (h 2 =0.00, p=0.494) or general psychopathology (h 2 =0.21, p=0.040). Externalizing showed genetic overlap with face memory (ρ g =-0.412, p=0.004), verbal reasoning (ρ g =-0.485, p=0.001), spatial reasoning (ρ g =-0.426, p=0.010), motor speed (ρ g =0.659, p=1x10 -4 ), verbal knowledge (ρ g =-0.314, p=0.002), and general cognitive ability (g)(ρ g =-0.394, p=0.002). Gene × Age analyses revealed decreasing genetic variance (γ g = -0.146, p = 0.004), and increasing environmental variance (γ e = 0.059, p = 0.009) on externalizing.Conclusions Cognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.

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“…Furthermore, parent-offspring trio studies of de novo CNVs and SNVs will contribute in disease etiology, since de novo aberrations in genome are more likely deleterious [28]. Identification of disease-associated genes and knowledge of their molecular functions will lead to better understanding of their disease pathology and hopefully enable better diagnostic and treatment [47].…”

Section: Discussionmentioning

confidence: 99%

“…In study of Thapar et al found CNVs in ADHD patients were enriched in genes for which it was previously known to be involved in SCZ, Fragile X ID, and partly with autism [50]. More recently 26 ADHD-associated candidate genes were identified that share common biological topic such as transcription, mitochondrial biology, mRNA metabolism, and cytoskeleton [47].…”

Section: The Importance Of Cnv In Diagnostics Of Adhdmentioning

confidence: 99%

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Role of Copy Number Variations in ADHD

Krgovic¹

2021

ADHD - From Etiology to Comorbidity

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Copy number variations (CNV) have an important role in etiology of neurodevelopmental disorders (NDD). Among them, individuals with attention-deficit and hyperactivity disorders (ADHD) have 1.33 times higher overall rate of CNVs larger than 100 kb compared to healthy controls. These CNVs are often shared with other NDDs and neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD), although duplications of 15q13.3 and 16p13.11 have been found enriched in ADHD cohorts. CNVs provide new opportunities for studying and management of psychiatric disorders including ADHD. Therefore this chapter provides a brief overview of the literature on this topic and presents the benefits of CNV genetic diagnostics in ADHD patients.

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From Rare Copy Number Variants to Biological Processes in ADHD

Cited by 35 publications

References 86 publications

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

Genetic influences on externalizing psychopathology overlap with cognitive functioning and show developmental variation

Role of Copy Number Variations in ADHD

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