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

Guðmundsson, Ólafur Ó.; Walters, G. Bragi; Ingason, Andrés; Johansson, Stefan; Zayats, Tetyana; Athanasiu, Lavinia; Sønderby, Ida Elken; Gústafsson, Ómar; Nawaz, Muhammad Sulaman; Jónsson, Guðbjörn F.; Jönsson, Lina; Knappskog, Per-Morten; Ingvarsdottir, Ester; Davíðsdóttir, Katrín; Djurovic, Srdjan; Knudsen, Gun Peggy; Askeland, Ragna Bugge; Haraldsdóttir, Gyða S.; Baldursson, Gísli; Magnússon, Páll; Sigurðsson, Engilbert; Guðbjartsson, Daníel F.; Stefánsson, Hreinn; Andreassen, Ole A.; Haavik, Jan; Reichborn‐Kjennerud, Ted; Stefánsson, Kāri

doi:10.1038/s41398-019-0599-y

Cited by 96 publications

(103 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The limited phenotypic data in the SZ group did not allow to investigate the relationship between deletion FC-signatures and cognitive traits in this sample. Lack of similarity observed for ADHD is line with the small association between 16p11.2 CNVs and ADHD but is discordant with the association reported for 22q11.2 5 . ADHD has a smaller effect size than SZ and ASD, which may have limited our analysis 41 .…”

Section: Limitationssupporting

confidence: 67%

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

Moreau

Urchs

Orban

et al. 2019

Preprint

View full text Add to dashboard Cite

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) networks remains unclear.We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify major dimensions contributing to complex idiopathic conditions. CNVs had large mirror effects on FC at the global and regional level, and their effect-sizes were twice as large as those of idiopathic conditions. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD.Individuals with higher similarity to deletion FC-signatures exhibited worse behavioral and cognitive symptoms. These seemingly distinct neuropsychiatric mutations showed similar gene co-expression patterns and converged on FC dimensions, that may represent mechanistic building blocks shared across idiopathic conditions.

show abstract

Section: Limitationssupporting

confidence: 67%

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

Moreau

Urchs

Orban

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Attention deficit hyperactivity disorder (ADHD) is a highly heritable (~70%), common and impairing neurodevelopmental disorder with a complex genetic architecture 1 . Recent case-control genome-wide studies point to the involvement of thousands of relatively common single-nucleotide polymorphisms 2 , very rare proteintruncating sequence variants and likely pathogenic missense mutations 3 , as well as large, rare copy number variants (CNVs) [4][5][6] . Although all of these classes of variant are associated with ADHD risk, robustly implicating specific risk alleles is an ongoing process.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

View full text Add to dashboard Cite

Recent 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. Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200 kb) CNVs and identified those calls that were present in the proband and absent in both biological parents. In 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 four 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. Our 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.

show abstract

“…Genomics studies in psychiatric populations have implicated the 15q11.2 BP1-BP2 deletion with a wide range of psychiatric, neurodevelopmental disorders, including a 2-to 4-fold increased risk for schizophrenia [205,206], a finding that has been replicated in many subsequent studies [92,179,[207][208][209][210]. Additionally, 15q11.2 deletions, and duplications, predispose individuals to a 5-fold risk of epilepsy [211], developmental and ID [212][213][214], attention deficit hyperactivity disorder [215], major depression [216], and autism [187,217] [for further review, see 182,186]. Meanwhile, common variants in CYFIP1 have been reported to increase the risk for ASD [218,219].…”

Section: Cyfip1 Variants In Psychiatric Genomic Studiesmentioning

confidence: 99%

FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

et al. 2020

View full text Add to dashboard Cite

There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (FMR1) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (CYFIP1) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of FMR1 and CYFIP1 to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.

show abstract

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

Cited by 96 publications

References 51 publications

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

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

FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

Contact Info

Product

Resources

About