The role of ADHD associated genes in neurodevelopment

Dark, Callum; Homman‐Ludiye, Jihane; Bryson-Richardson, Robert J.

doi:10.1016/j.ydbio.2018.03.023

Cited by 76 publications

(61 citation statements)

References 221 publications

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“…The hub regions shared by 3 pairs of disorders also overlapped with a handful of interesting candidate genes. SORCS3 (Figure 5B) is highly expressed in the CA1 region of the hippocampus, and is involved in synaptic depression and spatial learning ability 56,57 . It is also known to play an important role in protein networks associated with PICK1, NGF, and PDGF-BB 58,59 which have been implicated in ADHD, ASD, MDD, and SCZ [60][61][62][63] .…”

Section: Discussionmentioning

confidence: 99%

Detecting Local Genetic Correlations with Scan Statistics

Guo

et al. 2019

Preprint

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Genetic correlation analysis has quickly gained popularity in the past few years and provided insights into the genetic etiology of numerous complex diseases. However, existing approaches oversimplify the shared genetic architecture between different phenotypes and cannot effectively identify precise genetic regions contributing to the genetic correlation. In this work, we introduce LOGODetect, a powerful and efficient statistical method to identify small genome segments harboring local genetic correlation signals. LOGODetect automatically identifies genetic regions showing consistent associations with multiple phenotypes through a scan statistic approach. It uses summary association statistics from genome-wide association studies (GWAS) as input and is robust to sample overlap between studies. Applied to five phenotypically distinct but genetically correlated psychiatric disorders, we identified 49 non-overlapping genome regions associated with multiple disorders, including multiple hub regions showing concordant effects on more than two disorders. Our method addresses critical limitations in existing analytic strategies and may have wide applications in post-GWAS analysis.

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Section: Discussionmentioning

confidence: 99%

Detecting Local Genetic Correlations with Scan Statistics

Guo

et al. 2019

Preprint

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“…Observations in patients consistently reveal volume reduction in many brain regions, in particular those involved in attention, including the parietal and temporal lobes, the prefrontal and cingulate cortices (for a summary of the regions affected see Dark et al. ). Volume reduction has also been observed in the thalamus, specifically the pulvinar complex (Ivanov et al.…”

Section: Association With Neurodevelopmental Disordersmentioning

confidence: 99%

“…Although the aetiology of the disorder is still unknown, studies have demonstrated the contribution of environmental and genetic factors (for review Dark et al. ). Observations in patients consistently reveal volume reduction in many brain regions, in particular those involved in attention, including the parietal and temporal lobes, the prefrontal and cingulate cortices (for a summary of the regions affected see Dark et al.…”

Section: Association With Neurodevelopmental Disordersmentioning

confidence: 99%

The medial pulvinar: function, origin and association with neurodevelopmental disorders

Homman‐Ludiye

Bourne

2019

Journal of Anatomy

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The pulvinar is primarily referred to for its role in visual processing. However, the 'visual pulvinar' only encompasses the inferior and lateral regions of this complex thalamic nucleus. The remaining medial portion (medial pulvinar, PM) establishes distinct cortical connectivity and has been associated with directed attention, executive functions and working memory. These functions are particularly impaired in neurodevelopmental disorders, including schizophrenia and attention deficit and hyperactivity disorder (ADHD), both of which have been associated with abnormal PM architecture and connectivity. With these disorders becoming more prevalent in modern societies, we review the literature to better understand how the PM can participate in the pathophysiology of cognitive disorders and how a better understanding of the development and function of this thalamic nucleus, which is most likely exclusive to the primate brain, can advance clinical research and treatments.

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“…Previous work done by Zimmerman et al [ 31 ] showed a 16% decrease in excitatory synapses in mice engineered to display reduced Cfl1 in the striatum, and the High-Active mice displayed reduced Cfl1 ( Fig 2B ). Human ADHD has been associated with genetic variants in synapse-related genes [ 54 ] including synaptophysin [ 55 ]. The genetic association between Lphn3 and ADHD in human populations has been suggested to result from the allele’s effects on synapse stabilization.…”

Section: Discussionmentioning

confidence: 99%

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Sorokina¹,

Saul²,

Goncalves³

et al. 2018

PLoS ONE

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Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines.

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The role of ADHD associated genes in neurodevelopment

Cited by 76 publications

References 221 publications

Detecting Local Genetic Correlations with Scan Statistics

Detecting Local Genetic Correlations with Scan Statistics

The medial pulvinar: function, origin and association with neurodevelopmental disorders

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

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