Gathering the Clues to Rare Gene Variants Contributing To Schizophrenia

Findings from two new studies in Biological Psychiatry

Philadelphia, PA, February 20, 2014

Schizophrenia has long been known to be highly heritable and is present in approximately 1% of the population. Researchers have been following two paths in their pursuit of identifying schizophrenia risk genes.

Initially, they studied common gene variants that, individually, only increase the risk for schizophrenia by a few percent, perhaps increasing the likelihood of developing schizophrenia from a 10 out of a 1000 chance to an 11 or 12 out of a 1000 chance.

More recently, research has identified gene variants that are rare in the population but, when present, more substantially increase the risk for developing schizophrenia. For example, in the current issue of Biological Psychiatry, a large collaborating group of international scientists, led by Dr. Jennifer Mulle, an Assistant Professor at Emory, report a 1.4 megabase duplication on chromosome 7 (7q11.23) that increases the risk for schizophrenia over 10 times, i.e., to 100 out of a 1000 chance (10%).

"We also found it interesting that three different disorders (schizophrenia, autism, and intellectual development) that strike at different times and present in different ways, have genetic links to this same region on chromosome 7," commented Mulle. "Our findings support the notion of a neuro-developmental link between these disorders."

In this same issue, Dr. George Kirov at Cardiff University and colleagues scanned the genome for copy number gene variants, i.e., where abnormal numbers of gene copies exist. They studied 70 of these variants, all previously implicated in schizophrenia and/or early-onset developmental disorders, such as developmental delay, intellectual deficit and autism spectrum disorders (DD/ID/ASD). They then compared the risk for carriers of these variants to develop one or more of these disorders, i.e. their genetic penetrance.

"The result might be unexpected for many: the penetrance for schizophrenia is several times lower than for the group of DD/ID/ASD. The total penetrance for any of these disorders is quite high, ranging from 10% for duplications at 16p13.11 to nearly 100% for the velocardiofacial syndrome region on chromosome 22. These findings will have implications for genetic counselling of carriers," said Kirov.

"It seems that we are at a critical point in the genetics of schizophrenia – the identification of rare gene variants that substantially increase the risk for schizophrenia," said Dr. John Krystal, Editor of Biological Psychiatry. "However, we have a very limited understanding of how these genes alter brain development to produce schizophrenia and other disorders. This knowledge would seem to hold clues about mechanisms of prevention and treatment."

In addition, scientists do not yet understand why the genetics of schizophrenia is not tightly aligned with the symptoms of schizophrenia. In other words, gene variants that increase the risk for schizophrenia increase the risk for other disorders, such as developmental delay, autism, and bipolar disorder.

"The failure of our genome to follow DSM-V is not simply a shortcoming of our diagnostic manual, rather it is yet another reminder that there are fundamental aspects of the biology of psychiatric disorders that we do not understand," added Krystal.

The articles are "Reciprocal Duplication of the Williams-Beuren Syndrome Deletion on Chromosome 7q11.23 Is Associated with Schizophrenia" by Jennifer Gladys Mulle, Ann E. Pulver, John A. McGrath, Paula S. Wolyniec, Anne F. Dodd, David J. Cutler, Jonathan Sebat, Dheeraj Malhotra, Gerald Nestadt, Donald F. Conrad, Matthew Hurles, Chris P. Barnes, Masashi Ikeda, Nakao Iwata, Douglas F. Levinson, Pablo V. Gejman, Alan R. Sanders, Jubao Duan, Adele A. Mitchell, Inga Peter, Pamela Sklar, Colm T. O'Dushlaine, Detelina Grozeva, Michael C. O'Donovan, Michael J. Owen, Christina M. Hultman, Anna K. Kähler, Patrick F. Sullivan, The Molecular Genetics of Schizophrenia Consortium, George Kirov, and Stephen T. Warren (doi: 10.1016/j.biopsych.2013.05.040) and "The Penetrance of Copy Number Variations for Schizophrenia and Developmental Delay" by George Kirov, Elliott Rees, James T.R. Walters, Valentina Escott-Price, Lyudmila Georgieva, Alexander L. Richards, Kimberly D. Chambert, Gerwyn Davies, Sophie E. Legge, Jennifer L. Moran, Steven A. McCarroll, Michael C. O'Donovan, and Michael J. Owen (doi: 10.1016/j.biopsych.2013.07.022). The articles appear in Biological Psychiatry, Volume 75, Issue 5 (March 1, 2014), published by Elsevier.


# # #


Notes for editors

Full text of the article is available to credentialed journalists upon request; contact Rhiannon Bugno at +1 214 648 0880 or Biol.Psych@utsouthwestern.edu. Journalists wishing to interview the authors may contact Dr. Jennifer Mulle at +1 404 727 0406 or jmulle@emory.edu and George Kirov at +44 29 20 688 465 or kirov@cardiff.ac.uk.

The authors' affiliations, and disclosures of financial and conflicts of interests are available in their respective articles.

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 4th out of 135 Psychiatry titles and 13th out of 251 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2012 Impact Factor score for Biological Psychiatry is 9.247.

About Elsevier

Elsevier is a world-leading provider of information solutions that enhance the performance of science, health, and technology professionals, empowering them to make better decisions, deliver better care, and sometimes make groundbreaking discoveries that advance the boundaries of knowledge and human progress. Elsevier provides web-based, digital solutions — among them ScienceDirect, Scopus, Elsevier Research Intelligence, and ClinicalKey — and publishes nearly 2,200 journals, including The Lancet and Cell, and over 25,000 book titles, including a number of iconic reference works.

The company is part of Reed Elsevier Group PLC, a world leading provider of professional information solutions in the Science, Medical, Legal and Risk and Business sectors, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Media contact
Rhiannon Bugno
Editorial Office
+1 214 648 0880
Biol.Psych@utsouthwestern.edu