Evidence that duplications of 22q11.2 protect against schizophrenia

Rees, Elliott; Kirov, George; Sanders, Alan R.; Walters, James; Chambert, Kimberly; Shi, Jianxin; Szatkiewicz, Jin P.; Ó'Dúshláine, Colm; Richards, Alexander; Green, Elaine Karen; Jones, Ian; Davies, G.; Legge, Sophie E.; Moran, Jennifer L.; Pato, Carlos N.; Pato, Michele T.; Genovese, Giulio; Levinson, Douglas F.; Duan, Jubao; Moy, Winton; Göring, Harald H.H.; Morris, Derek W.; Cormican, Paul; Kendler, Kenneth S.; O'Neill, F. Anthony; Riley, Brien P.; Gill, Michael; Corvin, Aiden; Craddock, Nicholas John; Sklar, Pamela; Hultman, Christina; Sullivan, Patrick F.; Gejman, Pablo V.; McCarroll, Steven A.; O'Donovan, Michael Conlon

doi:10.1038/mp.2013.156

Cited by 132 publications

(111 citation statements)

References 22 publications

(29 reference statements)

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“…ARHGEF10, Rho guanine nucleotide exchange factor (GEF) 10 is highly expressed in the central and peripheral nervous systems. In affected members of a family with slowed motor and sensory nerve conduction velocities with autosomal dominant inheritance, Verhoeven et al [21][22][23] identified a heterozygous missense mutation in a conserved region of the ARHGEF10 gene. The authors suggested that ARHGEF10 played a role in developmental myelination of peripheral nerves.…”

Section: Discussionmentioning

confidence: 99%

Further Evidence for Dlgap2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene

Poquet¹,

Faivre²,

Chehadeh³

et al. 2017

Autism Open Access

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Autism spectrum disorders are classified as neurodevelopmental disorders characterised by diminished social communication and interaction. The core symptoms typically coexist with other medical conditions such as intellectual disability. The involvement of rare copy number variations of varying expressivity and penetrance as risk factors in autism spectrum disorders/intellectual disability phenotypes has been highlighted in large series. The DLGAP2 gene, whose glutamatergic postsynaptic density product may play a role in synaptogenesis and plasticity, has been identified as a novel candidate on the basis of 2 de novo duplications in sporadic non-syndromic autism spectrum disorders/intellectual disability males. It has also been suggested that increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia spectrum disorders. Based on these results and after fine phenotyping of another patient with a de novo duplication involving DLGAP2 and presenting with autism spectrum disorder intersecting early-onset schizophrenia spectrum disorder, we gathered an international series of 9 cases (6 families) via international data sharing. Four sporadic males presented with autism spectrum disorders and one had other neurodevelopmental disorders. A family with 4 females displayed intellectual disability (2/4) and specific learning disorder (2/4). This study supports the hypothesis that rare copy number variations encompassing DLGAP2 with incomplete penetrance and variable expressivity could predispose to a broad range of early-onset neurodevelopmental disorders trajectories including autism spectrum disorders/intellectual disability, highlighting the existence of common predisposing factors to these overlapping phenotypic spectrums.

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Section: Discussionmentioning

confidence: 99%

Further Evidence for Dlgap2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene

Poquet¹,

Faivre²,

Chehadeh³

et al. 2017

Autism Open Access

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“…Consequently, de novo CNVs show a pattern of asymmetric sharing in which they are observed in multiple neuropsychiatric disorders, but are particularly prevalent in a subset of disorders. Most CNVs show this asymmetric sharing: 15q11.2-13.1 duplications disproportionately increase the risk of ASD, 22q11.2 deletions increase the schizophrenia risk more than ASD risk, and 22q11.2 duplications predominantly increase ID risk and may even be protective against schizophrenia [82].…”

Section: Trunk and Branchesmentioning

confidence: 99%

Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

et al. 2014

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Copy number variants (CNVs) have been identified as a major risk factor in neuropsychiatric disorders. In this review, we describe the phenotypes and syndromic features associated with CNVs at four of the bestcharacterized risk loci for these disorders: 15q11.2-13.1, 22q11.2, 16p11.2, and 7q11.23. By considering the reported prevalence of these CNVs in autism, intellectual disability, schizophrenia, and controls, we demonstrate a pattern of asymmetric shared risk in which CNVs increase the risk of multiple disorders but to differing degrees. This asymmetric risk sharing is incompatible with a model in which CNVs observed in autism or schizophrenia are secondary to a reduction in IQ, but favors a more complex relationship between individual CNVs and specific neuropsychiatric phenotypes. Finally, we discuss how the lessons learned from CNVs in neuropsychiatric disorders will translate to the expanding list of genes being associated with these disorders through exome sequencing.

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“…These deletions or duplications of chromosomal regions often span multiple genes and can either increase risk or protect from diagnosis, presumably by altering the 'dosing' of the genes contained within the variant region (Grozeva et al, 2010;International Schizophrenia C, 2008;Stefansson et al, 2008). For example, 22q11 hemideletion is associated with high rates of schizophrenia (Gothelf et al, 1997;Karayiorgou et al, 2010;Murphy et al, 1999), whereas 22q11 duplication may protect against schizophrenia diagnosis (Rees et al, 2014), suggesting that expression levels of specific genes are critical to normal and pathological brain development.…”

Section: Introductionmentioning

confidence: 99%

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

Schmidt

Mirnics

2014

Neuropsychopharmacol

188

130

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The origins of schizophrenia have eluded clinicians and researchers since Kraepelin and Bleuler began documenting their findings. However, large clinical research efforts in recent decades have identified numerous genetic and environmental risk factors for schizophrenia. The combined data strongly support the neurodevelopmental hypothesis of schizophrenia and underscore the importance of the common converging effects of diverse insults. In this review, we discuss the evidence that genetic and environmental risk factors that predispose to schizophrenia disrupt the development and normal functioning of the GABAergic system.

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Evidence that duplications of 22q11.2 protect against schizophrenia

Cited by 132 publications

References 22 publications

Further Evidence for Dlgap2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene

Further Evidence for Dlgap2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene

Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

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