scholarly journals An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Leandro de Araújo Lima ◽  
Ana Cecília Feio-dos-Santos ◽  
Sintia Iole Belangero ◽  
Ary Gadelha ◽  
Rodrigo Affonseca Bressan ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Integrative Approach ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Hyperactivity Disorder ◽  
New Genes

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

scholarly journals A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Joanna Martin ◽  
Grace Hosking ◽  
Megan Wadon ◽  
Sharifah Shameem Agha ◽  
Kate Langley ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Hyperactivity Disorder

scholarly journals Glutamatergic copy number variants and their role in attention‐deficit/hyperactivity disorder

2014 ◽  
Vol 165 (6) ◽  
pp. 502-509 ◽  
Author(s):  
Glaucia Chiyoko Akutagava‐Martins ◽  
Angelica Salatino‐Oliveira ◽  
Julia P. Genro ◽  
Verônica Contini ◽  
Guilherme Polanczyk ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Copy Number ◽  
Copy Number Variants ◽  
Hyperactivity Disorder

Genetics of Schizophrenia and Bipolar Disorder

2013 ◽  
pp. 232-246 ◽  
Author(s):  
Pamela Sklar
Keyword(s):  
Bipolar Disorder ◽  
Copy Number ◽  
Psychotic Disorders ◽  
De Novo ◽  
Copy Number Variants ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Sequencing Studies ◽  
Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. The explosion of strong and convincing genetic evidence indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. There is a role for rare single nucleotide variation as well as de novo genetic variation being pointed to in new sequencing studies, but their overall contribution to risk is less clear. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, there is evidence for polygenicity and as yet no deep sequencing surveys have been published. Several intriguing biological pathways are suggested by these genetic findings related to microRNAs and calcium channel signaling. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder. Translating these results into biological and etiological understanding has not yet advanced, and will likely only do so when experimental methods are developed than can address the large numbers of genes and variants within them that, along with environmental and stochastic effects, result in the development of disease for a particular person.

scholarly journals A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

2019 ◽  
Author(s):  
Joanna Martin ◽  
Grace Hosking ◽  
Megan Wadon ◽  
Sharifah Shameem Agha ◽  
Kate Langley ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Case Control ◽  
Genetic Studies ◽  
Hyperactivity Disorder ◽  
Risk Alleles ◽  
Tourette Disorder

AbstractBackgroundRecent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability, and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD.MethodsChildren with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200kb) CNVs and identified those calls that were present in the proband and absent in both biological parents.ResultsIn 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at 4 genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies.ConclusionsOur study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.

scholarly journals Clinical and cognitive characteristics of children with attention-deficit hyperactivity disorder, with and without copy number variants

2011 ◽  
Vol 199 (5) ◽  
pp. 398-403 ◽  
Author(s):  
Kate Langley ◽  
Joanna Martin ◽  
Sharifah Shameem Agha ◽  
Charlotte Davies ◽  
Evangelia Stergiakouli ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Intellectual Disability ◽  
Attention Deficit ◽  
Copy Number ◽  
Copy Number Variants ◽  
Rare Cnvs ◽  
Atypical Form ◽  
Hyperactivity Disorder ◽  
Significant Difference ◽  
Developmental Features

BackgroundSubmicroscopic, rare chromosomal copy number variants (CNVs) contribute to neurodevelopmental disorders but it is not known whether they define atypical clinical cases.AimsTo identify whether large, rare CNVs in attention-deficit hyperactivity disorder (ADHD) are confined to a distinct clinical subgroup.MethodA total of 567 children with ADHD aged 5–17 years were recruited from community clinics. Psychopathology was assessed using the Child and Adolescent Psychiatric Assessment. Large, rare CNVs (>500 kb, <1% frequency) were defined from single nucleotide polymorphism data.ResultsCopy number variant carriers (13.6%) showed no differences from non-carriers in ADHD symptom severity, symptom type, comorbidity, developmental features, family history or pre-/ perinatal markers. The only significant difference was a higher rate of intellectual disability (24% v. 9%, χ2 = 15.5, P = 0.001). Most CNV carriers did not have intellectual disability.ConclusionsLarge, rare CNVs are not restricted to an atypical form of ADHD but may be more highly enriched in children with cognitive problems.

Basic principles of genetic disease

ESC CardioMed ◽  
2018 ◽  
pp. 669-671
Author(s):  
Eric Schulze-Bahr
Keyword(s):  
Genetic Disease ◽  
Copy Number ◽  
Copy Number Variants ◽  
Single Nucleotide Variants ◽  
Individual Genome ◽  
Base Pairs ◽  
Single Nucleotide ◽  
Basic Principles ◽  
Bona Fide ◽  
Genomic Regions

The human genome consists of approximately 3 billion (3 × 109) base pairs of DNA (around 20,000 genes), organized as 23 chromosomes (diploid parental set), and a small mitochondrial genome (37 genes, including 13 proteins; 16,589 base pairs) of maternal origin. Most human genetic variation is natural, that is, common or rare (minor allele frequency >0.1%) and does not cause disease—apart from every true disease-causing (bona fide) mutation each individual genome harbours more than 3.5 million single nucleotide variants (including >10,000 non-synonymous changes causing amino acid substitutions) and 200–300 large structural or copy number variants (insertions/deletions, up to several thousands of base-pairs) that are non-disease-causing variations and scattered throughout coding and non-coding genomic regions.

scholarly journals Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Olafur O. Gudmundsson ◽  
G. Bragi Walters ◽  
Andres Ingason ◽  
Stefan Johansson ◽  
Tetyana Zayats ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variant ◽  
Pleiotropic Effect ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Hyperactivity Disorder

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5–BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10−21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.

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