Copy number variants contribute to risk of “schizophrenia-like” bipolar disorder subtype

A genome-wide association study in Biological Psychiatry examines the role of copy number variants in subtypes of bipolar disorder


Philadelphia, January 24, 2019

A form of rare genomic structural variation called copy number variants (CNVs) may be more closely associated with schizophrenia than bipolar disorder. A new study published in Biological Psychiatry failed to find that 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, but 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 the 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,” said lead author Alexander Charney, MD, PhD, Icahn School of Medicine at Mount Sinai, New York.

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.

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Notes for editors
The article is "Contribution of rare copy number variants to bipolar disorder risk is limited to schizoaffective cases," by 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 (https://doi.org/10.1016/j.biopsych.2018.12.009). It appears in Biological Psychiatry, published by Elsevier.

Copies of this paper are available to credentialed journalists upon request; please contact Rhiannon Bugno at Biol.Psych@sobp.org or +1 214 648 0880. Journalists wishing to interview the authors may contact Alexander Charney at alexander.charney@mssm.edu or Douglas Ruderfer at douglas.ruderfer@vanderbilt.edu.

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry
Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 6th out of 142 Psychiatry titles and 9th out of 261 Neurosciences titles in the Journal Citations Reports® published by Clarivate Analytics. The 2017 Impact Factor score for Biological Psychiatry is 11.982. www.sobp.org/journal

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