Is There Such A Thing As “Pure” Autism?

Genetic analysis from a new study in Biological Psychiatry says no

Philadelphia, PA, April 20, 2015

The search for genes that contribute to the risk for autism has made tremendous strides over the past 3 years. As this field has advanced, investigators have wondered whether the diversity of clinical features across patients with autism reflects heterogeneous sources of genetic risk.

If so, it was reasoned, then selecting a group of patients with very similar clinical features might result in a “purer”, i.e., more genetically homogenous, group of patients, making it easier to find autism-related genes.

Results from a new study published in the current issue of Biological Psychiatry now cast the validity of this view into doubt.

A large group of collaborating scientists used data from the Simons Simplex Collection, a project that extensively characterized 2576 autism simplex families, the largest such cohort amassed to date and for which the data is now available in a permanent repository.

The availability of this vast collection allowed the researchers to create phenotypic subgroups. In addition to the whole sample, this resulted in 11 subgroups of patients with similar diagnostic, IQ and symptom profiles. They then analyzed the genotypic data in an attempt to discover common genetic variants that confer risk for autism spectrum disorder.

Their results did not identify any genome-wide significant associations in the overall sample or in the phenotypic subgroups. This means that the extreme clinical variability observed among patients with autism spectrum disorder does not closely reflect common genetic variation.

“This study did not provide good evidence that selecting patients with similar symptoms results in a greater ability to find autism genes,” said Dr. John Krystal, Editor of Biological Psychiatry. “This might suggest that some of the clinical variability in autism arises from causes other than genetic vulnerability, such as epigenetic changes or other responses to the environment.”

It is important to note that these results are in alignment with the recent major change to autism’s diagnostic classification in the Diagnostic and Statistical Manual of Mental Disorders. In its 5th revision, several separate disorders, which included autism and Asperger’s disorder, were grouped into a single category termed autism spectrum disorder. That decision was based on growing evidence that the previously-distinct disorders actually reflected a continuum of severity of the same condition.

“We hope our study is a step towards a new paradigm for studies involving the relationship between psychiatric phenotypes and genotypes. Most previous studies have sought to refine or narrow phenotypic variation irrespective of its impact on genetic variation, with the expectation that such refinement will improve detection of genetic variation increasing risk for a disorder,” explained first author Dr. Pauline Chaste from Centre Hospitalier Sainte Anne in France.  

“Our results motivate another route, one targeting the genetic structure of traits and, for multiple traits, their genetic correlations,” Chaste added. “For autism, one important implication of our results is that our colleagues have done a very good job in first defining it; however, to make better headway on discovering genetic variation underlying risk, we believe refining phenotypes in light of their impact on genetic architecture will be essential.”

The article is “A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?” by Pauline Chaste, Lambertus Klei, Stephan J. Sanders, Vanessa Hus, Michael T. Murtha, Jennifer K. Lowe, A. Jeremy Willsey, Daniel Moreno-De-Luca, Timothy W. Yu, Eric Fombonne, Daniel Geschwind, Dorothy E. Grice, David H. Ledbetter, Shrikant M. Mane, Donna M. Martin, Eric M. Morrow, Christopher A. Walsh, James S. Sutcliffe, Christa Lese Martin, Arthur L. Beaudet, Catherine Lord, Matthew W. State, Edwin H. Cook Jr., and Bernie Devlin (doi: 10.1016/j.biopsych.2014.09.017). The article appears in Biological Psychiatry, Volume 77, Issue 9 (May 1, 2015), 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 Journalists wishing to interview the authors may contact Dr. Pauline Chaste at +33-1-45-65-61-05 or

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 135 Psychiatry titles and 14th out of 251 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2013 Impact Factor score for Biological Psychiatry is 9.472.

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, Research Intelligence and ClinicalKey— and publishes over 2,500 journals, including The Lancet and Cell, and more than 35,000 book titles, including a number of iconic reference works. Elsevier is part of RELX Group, a world-leading provider of information and analytics for professional and business customers across industries.

Media Contact
Rhiannon Bugno
Editorial Office
+1 214 648 0880