Effects of copy number variations on brain structure and risk for psychiatric illness: Large‐scale studies from the<scp>ENIGMA</scp>working groups on<scp>CNVs</scp>

Sønderby, Ida Elken; Ching, Christopher R. K.; Thomopoulos, Sophia I; Meer, Dennis van der; Sun, Daqiang; Villalon‐Reina, Julio E.; Agartz, Ingrid; Amunts, Katrin; Arango, Celso; Armstrong, Nicola J.; Ayesa-Arriola, Rosa; Bakker, Geor; Bassett, Anne S.; Boomsma, Dorret I.; Bülow, Robin; Butcher, Nancy J.; Calhoun, Vince D.; Caspers, Svenja; Chow, Eva W.C.; Cichon, Sven; Ciufolini, Simone; Craig, Michael C.; Crespo‐Facorro, Benedicto; Cunningham, Adam; Dale, Anders M.; Dazzan, Paola; Zubicaray, Greig I. de; Djurovic, Srdjan; Doherty, Joanne L.; Donohoe, Gary; Draganski, Bogdan; Durdle, Courtney A.; Ehrlich, Stefan; Emanuel, Beverly S.; Espeseth, Thomas; Fisher, Simon E.; Ge, Tian; Glahn, David C.; Grabe, Hans J.; Gur, Raquel E.; Gutman, Boris A.; Haavik, Jan; Håberg, Asta; Hansen, Laura A.; Hashimoto, Ryota; Hibar, Derrek P.; Holmes, Avram J.; Hottenga, Jouke‐Jan; Pol, Hilleke E. Hulshoff; Jalbrzikowski, Maria; Knowles, Emma; Kushan, Leila; Linden, David; Liu, Jingyu; Lundervold, Astri J.; Martin‐Brevet, Sandra; Martínez, Kenia; Mather, Karen A.; Mathias, Samuel R.; McDonald‐McGinn, Donna M.; McRae, Allan F.; Medland, Sarah E.; Moberget, Torgeir; Modenato, Claudia; Sánchez, Jennifer Monereo; Moreau, Clara; Mühleisen, Thomas W.; Paus, Tomáš; Pausová, Zdenka; Prieto, Carlos; Ragothaman, Anjanibhargavi; Reinbold, Céline S.; Marques, Tiago Reis; Repetto, Gabriela M.; Reymond, Alexandre; Roalf, David R.; Rodríguez-Herreros, Borja; Rucker, James; Sachdev, Perminder S.; Schmitt, J. Eric; Schofield, Peter R.; Silva, Ana Isabel; Stefánsson, Hreinn; Stein, Dan J.; Tamnes, Christian K.; Tordesillas‐Gutiérrez, Diana; Ulfarsson, Magnus O.; Vajdi, Ariana; Ent, Dennis van ‘t; Bree, Marianne B. M. van den; Vassos, Evangelos; Vázquez-Bourgon, Javier; Vila‐Rodriguez, Fidel; Walters, G. Bragi; Wang, Wen; Westlye, Lars T.; Wittfeld, Katharina; Zackai, Elaine H.; Stefánsson, Kári; Jacquemont, Sébastien; Thompson, Paul M.; Bearden, Carrie E.; Andreassen, Ole A.

doi:10.1002/hbm.25354

Cited by 45 publications

(40 citation statements)

References 183 publications

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“…For example, the study conducted by the Schizophrenia Working Group identified more than 100 independent loci associated with schizophrenia [38], suggesting that these variants contribute to the genetic susceptibility for primary psychosis [13]. Simultaneously, the detection of chromosomal rearrangements pointed out the implication of copy number variants-CNVs, small insertions and deletions (indels), as for the 22q11.2 microdeletion syndrome [31,[39][40][41]. Compared to single CNVs and indels, a smaller contribution to the risk of developing primary psychosis was found for each single nucleotide variation-SNV [17,19,39].…”

Section: Sociodemographic Risk Factorsmentioning

confidence: 99%

“…CNVs and indels are unique and rare in the general population. Instead, common in individuals with neurodevelopment disorders, including primary psychosis [17,40]. In fact, approximately 2.5% of schizophrenia cases have a known CNV [40], suggesting that these specific genetic variants might take part in the pathogenesis of primary psychosis.…”

Section: Sociodemographic Risk Factorsmentioning

confidence: 99%

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Primary Psychosis: Risk and Protective Factors and Early Detection of the Onset

et al. 2021

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Primary psychosis, which includes schizophrenia and other psychoses not caused by other psychic or physical conditions, has a strong impact worldwide in terms of disability, suffering and costs. Consequently, improvement of strategies to reduce the incidence and to improve the prognosis of this disorder is a current need. The purpose of this work is to review the current scientific literature on the main risk and protective factors of primary psychosis and to examine the main models of prevention, especially those related to the early detection of the onset. The conditions more strongly associated with primary psychosis are socio-demographic and economic factors such as male gender, birth in winter, ethnic minority, immigrant status, and difficult socio-economic conditions while the best-established preventive factors are elevated socio-economic status and an economic well-being. Risk and protective factors may be the targets for primordial, primary, and secondary preventive strategies. Acting on modifiable factors may reduce the incidence of the disorder or postpone its onset, while an early detection of the new cases enables a prompt treatment and a consequential better prognosis. According to this evidence, the study of the determinants of primary psychosis has a pivotal role in designing and promoting preventive policies aimed at reducing the burden of disability and suffering of the disorder.

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Section: Sociodemographic Risk Factorsmentioning

confidence: 99%

Section: Sociodemographic Risk Factorsmentioning

confidence: 99%

Primary Psychosis: Risk and Protective Factors and Early Detection of the Onset

et al. 2021

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“…A previous study found delta frequency (<4 Hz) EEG activity to be reduced in ADHD patients not using psychostimulant medication ( Furrer et al, 2017 ) the authors related their finding to reduced cortical grey matter, and delays in its maturation in ADHD ( Nakao et al, 2011 ; Shaw et al, 2006 ; Shaw et al, 2010 ). In contrast, imaging studies have suggested increased cortical grey matter thickness in 22q11.2DS, alongside changes in corticothalamic networks ( Lin et al, 2017 ; Sønderby et al, 2022 ; Sun et al, 2020 ), which may reduce across adolescence ( Schaer et al, 2009 ). This could therefore explain our finding of increased SW amplitude in 22q11.2DS, and its relationship with ADHD symptoms, as it has been previously demonstrated (in adults) that greater SW amplitude is associated with greater cortical thickness ( Dubé et al, 2015 ).…”

Section: Discussionmentioning

confidence: 94%

Sleep EEG in young people with 22q11.2 deletion syndrome: A cross-sectional study of slow-waves, spindles and correlations with memory and neurodevelopmental symptoms

Donnelly

Bartsch

Moulding

et al. 2022

eLife

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Background: Young people living with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS reflects convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions.Methods: In a cross-sectional design, we recorded high-density sleep EEG in young people (6-20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying associations between sleep architecture, EEG oscillations (spindles and slow waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep.Results: 22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During sleep, deletion carriers showed broadband increases in EEG power with increased slow-wave and spindle amplitudes, increased spindle frequency and density, and stronger coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that genotype effects on anxiety, ADHD and ASD were partially mediated by sleep EEG measures.Conclusions: This study provides a detailed description of sleep neurophysiology in 22q11.2DS, highlighting alterations in EEG signatures of sleep which have been previously linked to neurodevelopment, some of which were associated with psychiatric symptoms. Sleep EEG features may therefore reflect delayed or compromised neurodevelopmental processes in 22q11.2DS, which could inform our understanding of the neurobiology of this condition and be biomarkers for neuropsychiatric disorders.Funding: This research was funded by a Lilly Innovation Fellowship Award (UB), the National Institute of Mental Health (NIMH 5UO1MH101724; MvdB), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (MvdB), the Waterloo Foundation (918-1234; MvdB), the Baily Thomas Charitable Fund (2315/1; MvdB), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE) (MR/L011166/1; JH, MvdB and MO), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment 2 (IMAGINE-2) (MR/T033045/1; MvdB, JH and MO); Wellcome Trust Strategic Award 'Defining Endophenotypes From Integrated Neurosciences' Wellcome Trust (100202/Z/12/Z MO, JH). NAD was supported by a National Institute for Health Research Academic Clinical Fellowship in Mental Health and MWJ by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (202810/Z/16/Z). CE and HAM were supported by Medical Research Council Doctoral Training Grants (C.B.E. 1644194, H.A.M MR/K501347/1). HMM and UB were employed by Eli Lilly & Co during the study; HMM is currently an employee of Boehringer Ingelheim Pharma GmbH & Co KG.

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“…CNVs at proximal 16p11.2 are also associated with neurodevelopmental disorder, intellectual disability, attention-deficit hyperactivity disorder, depression, and autism [ 34 , 36 , 47 , 48 , 49 , 50 , 51 ]. Finally, CNVs at 22q11.2 are associated with congenital heart disease, neurodevelopmental disorders, intellectual disability, autism spectrum disorders, and other neuropsychiatric conditions [ 7 , 48 , 52 , 53 ]. Together, these data indicate that clinical manifestations of CNVs at the eight loci in this study are not limited to schizophrenia; they have pleiotropic clinical effects.…”

Section: Discussionmentioning

confidence: 99%

“…For example, to study pathophysiology and neuropsychiatric manifestations of the rare pathogenic CNVs associated with psychiatric disorders, two working groups were formed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium formed: the ENIGMA 22q11.2 Deletion Syndrome Working Group (22q-ENIGMA WG) and the ENIGMA-CNV Working Group (ENIGMA-CNV WG) [ 7 ]. These two working groups have reported the effects of several rare pathogenic CNVs, including 22q11.2 [ 7 ], 16p11.2 distal [ 8 ], 15q11.2 [ 9 ], and 1q21.2 [ 10 ], on brain structure, cognition, and neuropsychiatric symptoms, which has increased our understanding of the genetic etiology and neurobiology of schizophrenia and related psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Translational Study of Copy Number Variations in Schizophrenia

Cheng

Chien

Huang

et al. 2021

IJMS

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Rare copy number variations (CNVs) are part of the genetics of schizophrenia; they are highly heterogeneous and personalized. The CNV Analysis Group of the Psychiatric Genomic Consortium (PGC) conducted a large-scale analysis and discovered that recurrent CNVs at eight genetic loci were pathogenic to schizophrenia, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.23, 15q13.3, distal 16p11.2, proximal 16p11.2, and 22q11.2. We adopted a two-stage strategy to translate this knowledge into clinical psychiatric practice. As a screening test, we first developed a real-time quantitative PCR (RT-qPCR) panel that simultaneously detected these pathogenic CNVs. Then, we tested the utility of this screening panel by investigating a sample of 557 patients with schizophrenia. Chromosomal microarray analysis (CMA) was used to confirm positive cases from the screening test. We detected and confirmed thirteen patients who carried CNVs at these hot loci, including two patients at 1q21.1, one patient at 7q11.2, three patients at 15q13.3, two patients at 16p11.2, and five patients at 22q11.2. The detection rate in this sample was 2.3%, and the concordance rate between the RT-qPCR test panel and CMA was 100%. Our results suggest that a two-stage approach is cost-effective and reliable in achieving etiological diagnosis for some patients with schizophrenia and improving the understanding of schizophrenia genetics.

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Effects of copy number variations on brain structure and risk for psychiatric illness: Large‐scale studies from theENIGMAworking groups onCNVs

Cited by 45 publications

References 183 publications

Primary Psychosis: Risk and Protective Factors and Early Detection of the Onset

Primary Psychosis: Risk and Protective Factors and Early Detection of the Onset

Sleep EEG in young people with 22q11.2 deletion syndrome: A cross-sectional study of slow-waves, spindles and correlations with memory and neurodevelopmental symptoms

Translational Study of Copy Number Variations in Schizophrenia

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