Skip to main content
Full access
New Research
Published Online: 7 November 2014

Social Responsiveness, an Autism Endophenotype: Genomewide Significant Linkage to Two Regions on Chromosome 8

Abstract

Objective:

Autism spectrum disorder is characterized by deficits in social function and the presence of repetitive and restrictive behaviors. Following a previous test of principle, the authors adopted a quantitative approach to discovering genes contributing to the broader autism phenotype by using social responsiveness as an endophenotype for autism spectrum disorder.

Method:

Linkage analyses using scores from the Social Responsiveness Scale were performed in 590 families from the Autism Genetic Resource Exchange, a largely multiplex autism spectrum disorder cohort. Regional and genomewide association analyses were performed to search for common variants contributing to social responsiveness.

Results:

Social Responsiveness Scale scores were unimodally distributed in male offspring from multiplex autism families, in contrast with a bimodal distribution observed in female offspring. In correlated analyses differing by Social Responsiveness Scale respondent, genomewide significant linkage for social responsiveness was identified at chr8p21.3 (multipoint LOD=4.11; teacher/parent scores) and chr8q24.22 (multipoint LOD=4.54; parent-only scores), respectively. Genomewide or linkage-directed association analyses did not detect common variants contributing to social responsiveness.

Conclusions:

The sex-differential distributions of Social Responsiveness Scale scores in multiplex autism families likely reflect mechanisms contributing to the sex ratio for autism observed in the general population and form a quantitative signature of reduced penetrance of inherited liability to autism spectrum disorder among females. The identification of two strong loci for social responsiveness validates the endophenotype approach for the identification of genetic variants contributing to complex traits such as autism spectrum disorder. While causal mutations have yet to be identified, these findings are consistent with segregation of rare genetic variants influencing social responsiveness and underscore the increasingly recognized role of rare inherited variants in the genetic architecture of autism spectrum disorder.

Formats available

You can view the full content in the following formats:

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 266 - 275
PubMed: 25727539

History

Received: 5 May 2014
Revision received: 25 June 2014
Accepted: 18 July 2014
Published ahead of print: 7 November 2014
Published online: 1 March 2015
Published in print: March 01, 2015

Authors

Details

Jennifer K. Lowe, Ph.D.
From the Neurogenetics Program and Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles; the Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Interdepartmental Ph.D. Program in Neuroscience, Brain Research Institute, University of California, Los Angeles; the Departments of Psychiatry and Pediatrics, Washington University School of Medicine, St. Louis; and the Department of Human Genetics, University of California, Los Angeles.
Donna M. Werling, Ph.D.
From the Neurogenetics Program and Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles; the Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Interdepartmental Ph.D. Program in Neuroscience, Brain Research Institute, University of California, Los Angeles; the Departments of Psychiatry and Pediatrics, Washington University School of Medicine, St. Louis; and the Department of Human Genetics, University of California, Los Angeles.
John N. Constantino, M.D.
From the Neurogenetics Program and Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles; the Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Interdepartmental Ph.D. Program in Neuroscience, Brain Research Institute, University of California, Los Angeles; the Departments of Psychiatry and Pediatrics, Washington University School of Medicine, St. Louis; and the Department of Human Genetics, University of California, Los Angeles.
Rita M. Cantor, Ph.D.
From the Neurogenetics Program and Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles; the Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Interdepartmental Ph.D. Program in Neuroscience, Brain Research Institute, University of California, Los Angeles; the Departments of Psychiatry and Pediatrics, Washington University School of Medicine, St. Louis; and the Department of Human Genetics, University of California, Los Angeles.
Daniel H. Geschwind, M.D., Ph.D.
From the Neurogenetics Program and Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles; the Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles; the Interdepartmental Ph.D. Program in Neuroscience, Brain Research Institute, University of California, Los Angeles; the Departments of Psychiatry and Pediatrics, Washington University School of Medicine, St. Louis; and the Department of Human Genetics, University of California, Los Angeles.

Notes

Address correspondence to Dr. Geschwind ([email protected]).

Funding Information

National Institute of Mental Health10.13039/100000025: F31 MH093086, R01 MH071425, R01 MH081754, R01 MH100027, U24 MH081810
National Institute of Child Health and Human Development10.13039/100000071: HD042541, P30 HD062171, P50 HD055784
Supported by ACE Network grants R01 MH081754 and R01 MH100027 and ACE Center grants P50 HD055784 and R01 MH071425 to Dr. Geschwind; by grant R01 HD042541 and IDDRC Center grant P30 HD062171 to Dr. Constantino; and by NIMH grant F31 MH093086 to Dr. Werling. The Autism Genetic Resource Exchange is a program of Autism Speaks and was supported by NIMH grant U24 MH081810.Dr. Constantino receives royalties from Western Psychological Services for the commercial distribution of the Social Responsiveness Scale; however, no royalties were generated from research implementation of scale in the AGRE registry. Dr. Geschwind is a paid scientific advisor for Synapdx. All other authors report no financial relationships with commercial interests.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Full Text

View Full Text

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Purchase Options

Purchase this article to access the full text.

PPV Articles - American Journal of Psychiatry

PPV Articles - American Journal of Psychiatry

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share