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Abstract

Objective:

Both rare copy number variants (CNVs) and common single-nucleotide polymorphisms (SNPs) contribute to liability to schizophrenia, but their etiological relationship has not been fully elucidated. The authors evaluated an additive model whereby risk of schizophrenia requires less contribution from common SNPs in the presence of a rare CNV, and tested for interactions.

Method:

Genetic data from 21,094 case subjects with schizophrenia and 20,227 control subjects from the Psychiatric Genomics Consortium were examined. Three classes of rare CNVs were assessed: CNVs previously associated with schizophrenia, CNVs with large deletions ≥500 kb, and total CNV burden. The mean polygenic risk scores (PRSs) between study subjects with and without rare CNVs were compared, and joint effects of PRS and CNVs on schizophrenia liability were modeled by using logistic regression.

Results:

Schizophrenia case subjects carrying risk CNVs had a lower polygenic risk than case subjects without risk CNVs but a higher risk than control subjects. For case subjects carrying known risk CNVs, the PRS was diminished in proportion to the effect size of the CNV. The strongly associated 22q11.2 deletion required little added PRS to produce schizophrenia. Large deletions and increased CNV burden were also associated with lower polygenic risk in schizophrenia case subjects but not in control subjects or after removal of known risk CNV carriers.

Conclusions:

The authors found evidence for interactive effects of PRS and previously associated CNVs for risk for schizophrenia, and the results for large deletions and total CNV burden support an additive model. These findings offer insights into the genetic architecture of schizophrenia by illuminating how different established genetic risk factors act and interact to influence liability to schizophrenia.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 29 - 35
PubMed: 30392412

History

Received: 26 April 2017
Revision received: 1 April 2018
Revision received: 1 June 2018
Accepted: 29 June 2018
Published online: 5 November 2018
Published in print: January 01, 2019

Keywords

  1. Genome-wide Association Study
  2. Schizophrenia Risk Profile Score
  3. Copy Number Variation
  4. Structural Variation

Authors

Details

Sarah E. Bergen, Ph.D. [email protected]
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
Alexander Ploner, Ph.D.
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
Daniel Howrigan, Ph.D.
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
Michael C. O’Donovan, M.D., Ph.D.
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
Jordan W. Smoller, M.D., Sc.D.
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
Patrick F. Sullivan, M.D., F.R.A.N.Z.C.P.
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
Jonathan Sebat, Ph.D.
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
Benjamin Neale, Ph.D.
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
Kenneth S. Kendler, M.D.
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass.; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; the Department of Psychiatry, Harvard Medical School, and Massachusetts General Hospital, Boston; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill; the Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego; and the Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.

Notes

Send correspondence to Dr. Bergen ([email protected]).
Previously presented at the World Congress of Psychiatric Genetics, Toronto, Canada, October 16–20, 2015, and the 15th International Congress on Schizophrenia Research, Florence, Italy, March 28–April 1, 2015.

Competing Interests

The authors report no financial relationships with commercial interests.

Funding Information

National Institute of Mental Health10.13039/100000025: A Large-Scale Schizophrenia Association Study in S
Supported by NIMH grant U01 MH-094421.

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