Implication of a Rare Deletion at Distal 16p11.2 in Schizophrenia

Guha, Saurav; Rees, Elliott; Darvasi, Ariel; Ivanov, Dobril; Ikeda, Masashi; Bergen, Sarah E.; Magnusson, Patrik K. E.; Cormican, Paul; Morris, Derek W.; Gill, Michael; Cichon, Sven; Rosenfeld, Jeffrey; Lee, Annette; Gregersen, Peter K.; Kane, John M.; Malhotra, Anil K.; Rietschel, Marcella; Nöthen, Markus M.; Degenhardt, Franziska; Priebe, Lutz; Breuer, René; Strohmaier, Jana; Ruderfer, Douglas M.; Moran, Jennifer L.; Chambert, Kimberly; Sanders, Alan R.; Shi, Jianxin; Kendler, Kenneth S.; Riley, Brien P.; O’Neill, Tara; Walsh, Dermot; Malhotra, Dheeraj; Corvin, Aiden; Purcell, Shaun; Sklar, Pamela; Iwata, Nakao; Hultman, Christina M.; Sullivan, Patrick F.; Sebat, Jonathan; McCarthy, Shane; Gejman, Pablo V.; Levinson, Douglas F.; Owen, Michael John; Lencz, Todd; Kirov, George

doi:10.1001/2013.jamapsychiatry.71

Cited by 70 publications

(52 citation statements)

References 29 publications

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“…Further, the overall rates of disease-related CNVs in COS probands were compared with the published results in large cohort studies using Fisher’s exact test with adjustment for multiple comparisons. Finally, CNVs were screened for AOS patients 31,32 and the rate of disease-related CNVs was compared using Fisher’s exact test. All analyses were performed using the statistical package SAS V.9.2 (SAS Institute, Cary, NC, USA) and the two-sided P -values <0.05 were considered significant.…”

Section: Methodsmentioning

confidence: 99%

High rate of disease-related copy number variations in childhood onset schizophrenia

et al. 2013

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Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P = 0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P<0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5–3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3–1%) (P<0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.

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Section: Methodsmentioning

confidence: 99%

High rate of disease-related copy number variations in childhood onset schizophrenia

et al. 2013

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“…It has been suggested that the major driver of the neuroanatomical phenotypes may be the gene KCTD13 which has been implicated in long-term positioning and dendritic maturation of cerebral cortical neurons [43]. A more distal and smaller region on 16p11.2 has also been implicated in schizophrenia when deleted [44, 45], as well as in developmental delay and obesity [45]. The 2p16.3 deletion was first identified by comparative genome hybridization and disrupts the NRXN1 gene encoding neurexin 1 a presynaptic cell adhesion molecule which interacts with neuroligins to induce synapse formation and maturation [46, 47].…”

Section: High-penetrance Genetic Variationmentioning

confidence: 99%

Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novο variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory. Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups. Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes. The challenge is to apply this new knowledge to prevention and treatment and help patients. The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.

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“…CNVs at 16p11.2 (Guha et al 2013), 17p12 (Kirov et al 2009a) and17q12 (Moreno-De-Luca et al 2010) were confirmed in a recent meta-analysis (Rees et al 2014b).…”

Section: Cnvs Through Gwa Studiesmentioning

confidence: 85%

Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part II: Cognition, neuroimaging and genetics

Schmitt

Rujescu²,

Gawlik

et al. 2016

The World Journal of Biological Psychiatry

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Future studies should address the effects of treatment and stage of the disease more precisely and apply combinations of biomarker candidates. Although biomarkers for schizophrenia await validation, knowledge on candidate genomic and neuroimaging biomarkers is growing rapidly and research on this topic has the potential to identify psychiatric endophenotypes and in the future increase insight on individual treatment response in schizophrenia.

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Implication of a Rare Deletion at Distal 16p11.2 in Schizophrenia

Cited by 70 publications

References 29 publications

High rate of disease-related copy number variations in childhood onset schizophrenia

High rate of disease-related copy number variations in childhood onset schizophrenia

Recent Advances in the Genetics of Schizophrenia

Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part II: Cognition, neuroimaging and genetics

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