Genomic copy number variants contribute to cognitive impairment in the UK

Reports new study in Biological Psychiatry

Philadelphia, PA, June 28, 2017

Genetic alterations of rare deletions or duplications of small DNA segments, called copy number variants (CNVs), have been known to increase risk of neurodevelopmental disorders such as schizophrenia, autism spectrum disorder, and intellectual disability. Now, a new study in Biological Psychiatry reports that even in the absence of a disorder, people carrying a CNV associated with these disorders may have impaired cognition.

Led by Dr. George Kirov of Cardiff University MRC Centre for Neuropsychiatric Genetics & Genomics, UK, the study provides the largest analysis to date on the effects of CNVs on cognition in a general population — most previous studies have focused on disease populations. The findings help researchers understand the effects of neurodevelopmental genetic abnormalities, even when they don’t lead to the emergence of a disease.

“Psychiatric disorders are relatively extreme neuropsychiatric conditions. This study makes the case that CNVs that have been implicated in the risk for these disorders more directly produce subtle intellectual and functional changes that may be of great importance to these people and to society,” said Dr. John Krystal, Editor of Biological Psychiatry.

In the study, first author Dr. Kimberley Kendall, also of Cardiff University, and colleagues analyzed data from the UK Biobank, a repository of extensive demographic, health, and cognitive data from 500,000 adults. The first nearly 152,000 of those have also been genotyped and were included in the study. Kendall and colleagues focused on CNVs that have been statistically linked with risk of neurodevelop-mental disorders (neurodevelopmental CNVs), including 12 schizophrenia-associated CNVs and a group of 41 CNVs associated with other disorders.

In a comparison of performance on cognitive tests between adults with schizophrenia, carriers of neurodevelopmental CNVs who were otherwise healthy, and people who did not carry any CNVs in their genome (noncarriers), those with schizophrenia performed the worst. Performance of carriers fell in between noncarriers and people with schizophrenia. Carriers also had lower educational attainment and tended to have occupations requiring less skill or training. No differences were found between carriers of the 12 schizophrenia-associated CNVs versus carriers of the other neurodevelopmental CNVs.

However, there was a lot of overlap between the schizophrenia, carrier, and noncarrier groups. “The cognitive performance of carriers of schizophrenia-associated CNVs was indeed reduced, but the differences were subtle and a large proportion of CNV carriers appeared to function very well,” said Kirov, adding that many CNV carriers reached very high levels of academic achievement, and successfully obtain highly skilled or cognitively demanding occupations.

The findings fill gaps in the knowledge of the effects of CNVs in adults from the general population, and extend previous reports of incomplete penetrance, where adults carrying CNVs who don’t develop a disorder may still have an increased burden of cognitive impairments.

“The study hints at the huge potential of the UK Biobank for further research into the role of CNVs in human health and disease, and the opportunities it affords to study the effect of CNVs on carriers who are being followed up for many years for their psychiatric, cognitive and medical outcomes,” said Kirov.

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Notes for editors
The article is "Cognitive Performance Among Carriers of Pathogenic Copy Number Variants: Analysis of 152,000 UK Biobank Subjects," by Kimberley M. Kendall, Elliott Rees, Valentina Escott-Price, Mark Einon, Rhys Thomas, Jonathan Hewitt, Michael C. O’Donovan, Michael J. Owen, James T.R. Walters, and George Kirov (http://dx.doi.org/10.1016/j.biopsych.2016.08.014). It appears in Biological Psychiatry, volume 82, issue 2 (July 2017), published by Elsevier.

Copies of this paper are available to credentialed journalists upon request; please contact Rhiannon Bugno at Biol.Psych@UTSouthwestern.edu or +1 214 648 0880. Journalists wishing to interview the authors may contact George Kirov, Ph.D., at kirov@cardiff.ac.uk.

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

John H. Krystal, M.D., 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 5th out of 140 Psychiatry titles and 11th out of 256 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2015 Impact Factor score for Biological Psychiatry is 11.212.

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Media contact
Rhiannon Bugno
Editorial Office, Biological Psychiatry
+1 214 648 0880
Biol.Psych@UTSouthwestern.edu