Converging levels of analysis on a genomic hotspot for psychosis: Insights from 22q11.2 Deletion Syndrome

Schreiner, Matthew; Lázaro, María Teresa; Jalbrzikowski, Maria; Bearden, Carrie E.

doi:10.1016/j.neuropharm.2012.09.012

Cited by 29 publications

(28 citation statements)

References 196 publications

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“…Alternatively there may be a digenic phenomenon. One of these is likely to occur in 22q11.2 deletion syndrome, where there are many ohnologs, and a number of genes involved in neurotransmission, neuronal development, myelination, microRNA processing, and posttranslational protein modifications which could plausibly contribute to the neurobehavioral phenotypes (16). Most of the CNVs we examined contain multiple ohnologs, such as 16p13.11, with four ohnologs from nine genes in the critical region (Fig.…”

Section: Discussionmentioning

confidence: 99%

Ohnologs are overrepresented in pathogenic copy number mutations

McLysaght

Makino

Grayton

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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A number of rare copy number variants (CNVs), including both deletions and duplications, have been associated with developmental disorders, including schizophrenia, autism, intellectual disability, and epilepsy. Pathogenicity may derive from dosage sensitivity of one or more genes contained within the CNV locus. To understand pathophysiology, the specific disease-causing gene(s) within each CNV need to be identified. In the present study, we test the hypothesis that ohnologs (genes retained after ancestral whole-genome duplication events, which are frequently dosage sensitive) are overrepresented in pathogenic CNVs. We selected three sets of genes implicated in copy number pathogenicity: (i) genes mapping within rare disease-associated CNVs, (ii) genes within de novo CNVs under negative genetic selection, and (iii) genes identified by clinical array comparative genome hybridization studies as potentially pathogenic. We compared the proportion of ohnologs between these gene sets and control genes, mapping to CNVs not known to be disease associated. We found that ohnologs are significantly overrepresented in genes mapping to pathogenic CNVs, irrespective of how CNVs were identified, with over 90% containing an ohnolog, compared with control CNVs >100 kb, where only about 30% contained an ohnolog. In some CNVs, such as del15p11.2 (CYFIP1) and dup/del16p13.11 (NDE1), the most plausible prior candidate gene was also an ohnolog, as were the genes VIPR2 and NRXN1, each found in short CNVs containing no other genes. Our results support the hypothesis that ohnologs represent critical dosage-sensitive elements of the genome, possibly responsible for some of the deleterious phenotypes observed for pathogenic CNVs and as such are readily identifiable candidate genes for further study.

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Section: Discussionmentioning

confidence: 99%

Ohnologs are overrepresented in pathogenic copy number mutations

McLysaght

Makino

Grayton

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…These alterations might influence functional connectivity (Schreiner et al, 2013), and could be implicated in the observed cognitive and behavioral deficits. In particular, they may explain observed alterations in prepulse inhibition (Stark et al, 2008), which have also been reported in schizophrenia patients (Powell et al, 2009).…”

Section: The Role Of Dgcr8mentioning

confidence: 99%

MicroRNAs as the cause of schizophrenia in 22q11.2 deletion carriers, and possible implications for idiopathic disease: a mini-review

Forstner

Degenhardt

Schratt

et al. 2013

Front. Mol. Neurosci.

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The 22q11.2 deletion is the strongest known genetic risk factor for schizophrenia. Research has implicated microRNA-mediated dysregulation in 22q11.2 deletion syndrome (22q11.2DS) schizophrenia-risk. Primary candidate genes are DGCR8 (DiGeorge syndrome critical region gene 8), which encodes a component of the microprocessor complex essential for microRNA biogenesis, and MIR185, which encodes microRNA 185. Mouse models of 22q11.2DS have demonstrated alterations in brain microRNA biogenesis, and that DGCR8 haploinsufficiency may contribute to these alterations, e.g., via down-regulation of a specific microRNA subset. miR-185 was the top-scoring down-regulated microRNA in both the prefrontal cortex and the hippocampus, brain areas which are the key foci of schizophrenia research. This reduction in miR-185 expression contributed to dendritic and spine development deficits in hippocampal neurons. In addition, miR-185 has two validated targets (RhoA, Cdc42), both of which have been associated with altered expression levels in schizophrenia. These combined data support the involvement of miR-185 and its down-stream pathways in schizophrenia. This review summarizes evidence implicating microRNA-mediated dysregulation in schizophrenia in both 22q11.2DS-related and idiopathic cases.

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“…Mood disorders are present in 13–64%, predominantly represented by major depressive disorder (MDD) (Jolin et al 2009; Antshel et al 2010; Stoddard et al 2010; Fabbro et al 2012). Perhaps most remarkably, psychotic disorders are diagnosed in 23–32% of adults with 22q11DS (Murphy et al 1999; Gothelf et al 2007; Bassett & Chow, 2008; Green et al 2009; Schreiner et al 2013). …”

Section: Introductionmentioning

confidence: 99%

Psychiatric disorders in 22q11.2 deletion syndrome are prevalent but undertreated

et al. 2013

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Background Chromosome 22q11.2 deletion syndrome (22q11DS) is a common genetic disorder with high rates of psychosis and other psychopathologies, but few studies discuss treatment. Our aim was to characterize the prevalence and treatment of major psychiatric illnesses in a well-characterized sample of individuals with 22q11DS. Method This was a cross-sectional study of 112 individuals aged 8 to 45 years with a confirmed diagnosis of 22q11DS. Each participant was administered a modified Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) and the Structured Interview for Prodromal Syndromes (SIPS). Phenotypes assessed were threshold and subthreshold psychosis, depression, mania, generalized and separation anxiety, obsessions/compulsions, inattention/hyperactivity and substance use. Histories of mental health care and current psychotropic treatment were obtained. Results Psychopathology was common, with 79% of individuals meeting diagnostic criteria for a disorder at the time of assessment. Diagnoses of psychosis were made in 11% of cases, attenuated positive symptom syndrome (APS) in 21%, and 47% experienced significant subthreshold symptoms. Peak occurrence of psychosis risk was during adolescence (62% of those aged 12–17 years). Criteria for a mood disorder were met by 14%, for anxiety disorder 34% and for attention deficit hyperactivity disorder (ADHD) 31%. Mental health care had been received by 63% of individuals in their lifetime, but only 40% continued therapy and 39% used psychotropics. Antipsychotics were used by 42% of participants with psychosis and none of the participants with APS. Half of those at risk for psychosis were receiving no mental health care. Conclusions Psychopathology is common in 22q11DS but is not adequately treated or clinically followed. Particular attention should be paid to subthreshold psychotic symptoms, especially in adolescents.

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Converging levels of analysis on a genomic hotspot for psychosis: Insights from 22q11.2 Deletion Syndrome

Cited by 29 publications

References 196 publications

Ohnologs are overrepresented in pathogenic copy number mutations

Ohnologs are overrepresented in pathogenic copy number mutations

MicroRNAs as the cause of schizophrenia in 22q11.2 deletion carriers, and possible implications for idiopathic disease: a mini-review

Psychiatric disorders in 22q11.2 deletion syndrome are prevalent but undertreated

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