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Developmental Biology - Brain

CNVs Link to Schizophrenia

A study of the entire genome finds that copy number variants create a hybrid bipolar - schizophrenia disorder....

A form of rare gene structure variation called copy number variants (CNVs) may be more close in association to schizophrenia than with bipolar disorder. A new study published in Biological Psychiatry failed to find that copy number variations CNVs were associated broadly with risk for bipolar disorder. However, schizoaffective disorder, which is a hybrid of bipolar disorder and schizophrenia, had higher rates of CNVs compared with controls and other bipolar disorder subtypes.

"This study sheds important new light on the heterogeneity of bipolar disorder. It suggests an important new mechanism linking the biology of the most severely disabling form of bipolar disorder, schizoaffective disorder, to that of schizophrenia," said John Krystal MD, Editor of Biological Psychiatry.
Schizophrenia and bipolar disorder share many symptoms and genetic characteristics. However, the contribution of CNVs to genetic risk has only been confirmed in schizophrenia. Although some studies have previously reported increased CNVs in bipolar disorder, the new genome-wide study, which included 6,353 bipolar disorder cases and 8,656 controls, did not find strong support for any of these.

"In this paper, we can strongly conclude that these variants do not make a substantial contribution to risk of bipolar disorder broadly. However, we provide some evidence that CNVs do contribute to risk of a more 'schizophrenia-like' subtype of bipolar disorder and that this does not seem to be predominantly driven by symptoms of psychosis," said Douglas Ruderfer PhD, Vanderbilt University Medical Center, Tennessee, a senior author of the study.

No differences in CNVs were found between subtypes of bipolar I disorder with and without psychosis. The lack of connection between CNVs and psychosis led the authors to suggest that these rare genetic alterations may instead contribute to nuances that differentiate psychotic illnesses, including bipolar disorder with psychosis, schizoaffective bipolar, and schizophrenia.
"Our findings diverge from previous studies of common genetic variation that show genetic risk of schizophrenia is associated with risk of psychosis in bipolar disorder. These observations support the notion that different classes of genetic variation contribute to different domains of psychopathology, and suggest that the combination of genetic variants in a given individual create his or her unique symptom profile."

Alexander Charney MD PhD, Icahn School of Medicine at Mount Sinai, New York and lead author.

The symptoms of bipolar disorder vary between people, and the subtypes of the disorder are characterized by differences in strength and timing of the symptoms. The findings that CNVs are not associated with bipolar disorder as a whole, but rather a subtype of the disorder, provide insight into how symptom variation arises within the disease and highlights that considering these different subgroups as a single diagnosis might overlook important differences that define them.

Bipolar affective disorder (BPAD) and schizophrenia (SZ) are devastating psychiatric disorders that each affect about 1% of the population worldwide. Identification of new drug targets is an important step toward better treatment of these poorly understood diseases.

Genome-wide copy number variation (CNV) was assessed and variants were ranked by co-occurrence with disease in 48 BPAD families. Additional support for involvement of the highest-ranking CNV from the family-based analysis in psychiatric disease was obtained through analysis of 4084 samples with BPAD, SZ, or schizoaffective disorder. Finally, a pooled analysis of in-house and published datasets was carried out including 10,925 cases with BPAD, SZ, or schizoaffective disorder and 16,747 controls.

In the family-based analysis, an approximately 200 kilobase (kb) deletion in the first intron of the MAGI1 gene was identified that segregated with BPAD in a pedigree (six out of six affected individuals; parametric logarithm of the odds score = 1.14). In the pooled analysis, seven additional insertions or deletions over 100 kb were identified in MAGI1 in cases, while only two such CNV events were identified in the same gene in controls (p = .023; Fisher's exact test). Because earlier work had identified a CNV in the close relative MAGI2 in SZ, the study was extended to include MAGI2. In the pooled analysis of MAGI2, two large deletions were found in cases, and two duplications were detected in controls.

Results presented herein provide further evidence for a role of MAGI1 and MAGI2 in BPAD and SZ etiology.

Alexander William Charney, Eli A Stahl, Elaine K Green, Chia-Yen Chen, Jennifer L Moran, Kimberly Chambert, Richard A Belliveau, Jr, Liz Forty, Katherine Gordon-Smith, Phil H. Lee, Evelyn J Bromet, Peter F Buckley, Michael A Escamilla, Ayman H Fanous, Laura J Fochtmann, Douglas S Lehrer, Dolores Malaspina, Steohen R Marder, Christopher P Morley, Humberto Nicolini, Diana O Perkins, Jeffrey J Rakofsky, Mark H Rapaport, Helena Medeiros, Janet L Sobell, Lena Backlund, Sarah E Bergen, Anders Jureus, Martin Schalling, Paul Lichtenstein, James A Knowles, Katherine E Burdick, Ian Jones, Lisa A Jones, Christina M Hultman, Roy Perlis, Shaun M Purcell, Steven A McCarroll, Carlos N Pato, Michele T Pato, Arianna Di Florio, Nick Craddock, Mikael Landen, Jordan W. Smoller, Douglas M. Ruderfer, and Pamela Sklar.

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Jan 25, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

With each cell division, chromosome re-organization occurs (image). When errors happen, they are
called copy number variantions (CNVs) and can cause gene mutations. Unique classes of CNVs
contribute to different psychopathologies. New research suggests CNVs create unique symptoms
for a combination disorder of both bi-polar and schizophrenia. CNVs might explain why
there are so many symptom variations in schizophrenia. Image Credit:
How Cells Fight Chromosome Imbalance.

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