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Published Online: 7 September 2022

Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation

Guy Hindley, M.D. [email protected], Oleksandr Frei, Ph.D., Alexey A. Shadrin, Ph.D., Weiqiu Cheng, Ph.D., Kevin S. O’Connell, Ph.D., Romain Icick, M.D., Nadine Parker, Ph.D., … Show All … , Shahram Bahrami, Ph.D., Naz Karadag, M.Sc., Daniel Roelfs, M.Sc., Børge Holen, M.D., Aihua Lin, Ph.D., Chun C. Fan, M.D., Srdjan Djurovic, Ph.D., Anders M. Dale, Ph.D., Olav B. Smeland, M.D., and Ole A. Andreassen, M.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 179, Number 11
https://doi.org/10.1176/appi.ajp.21101051
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Abstract

Objective:

Mental disorders are heritable and polygenic, and genome-wide genetic correlations (rg) have indicated widespread shared genetic risk across multiple disorders and related traits, mirroring their overlapping clinical characteristics. However, rg may underestimate the shared genetic underpinnings of mental disorders and related traits because it does not differentiate mixtures of concordant and discordant genetic effects from an absence of genetic overlap. Using novel statistical genetics tools, the authors aimed to evaluate the genetic overlap between mental disorders and related traits when accounting for mixed effect directions.

Methods:

The authors applied the bivariate causal mixture model (MiXeR) to summary statistics for four mental disorders, four related mental traits, and height from genome-wide association studies (Ns ranged from 53,293 to 766,345). MiXeR estimated the number of “causal” variants for a given trait (“polygenicity”), the number of variants shared between traits, and the genetic correlation of shared variants (rgs). Local rg was investigated using LAVA.

Results:

Among mental disorders, ADHD was the least polygenic (5.6K “causal” variants), followed by bipolar disorder (8.6K), schizophrenia (9.6K), and depression (14.5K). Most variants were shared across mental disorders (4.4K–9.3K) and between mental disorders and related traits (5.2K–12.8K), but with disorder-specific variations in rg and rgs. Overlap with height was small (0.7K–1.1K). MiXeR estimates correlated with LAVA local rg (r=0.88, p<0.001).

Conclusions:

There is extensive genetic overlap across mental disorders and related traits, with mixed effect directions and few disorder-specific variants. This suggests that genetic risk for mental disorders is predominantly differentiated by divergent effect distributions of pleiotropic genetic variants rather than disorder-specific variants. This represents a conceptual advance in our understanding of the landscape of shared genetic architecture across mental disorders, which may inform genetic discovery, biological characterization, nosology, and genetic prediction.

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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
Volume 179 • Number 11 • November 01, 2022
Pages: 833 - 843
PubMed: 36069018

History

Received: 21 October 2021
Revision received: 5 May 2022
Accepted: 6 June 2022
Published online: 7 September 2022
Published in print: November 01, 2022

Keywords

  1. Genetics/Genomics
  2. Bipolar and Related Disorders
  3. Depressive Disorders
  4. Neurodevelopmental Disorders
  5. Attention Deficit Hyperactivity Disorder (ADHD)
  6. Schizophrenia Spectrum and Other Psychotic Disorders

Authors

Details

Guy Hindley, M.D. [email protected]
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Oleksandr Frei, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Alexey A. Shadrin, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Weiqiu Cheng, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Kevin S. O’Connell, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Romain Icick, M.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Nadine Parker, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Shahram Bahrami, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Naz Karadag, M.Sc.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Daniel Roelfs, M.Sc.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Børge Holen, M.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Aihua Lin, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Chun C. Fan, M.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Srdjan Djurovic, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Anders M. Dale, Ph.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Olav B. Smeland, M.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Ole A. Andreassen, M.D.
NORMENT Center, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo (Hindley, Frei, Shadrin, Cheng, O’Connell, Icick, Parker, Bahrami, Karadag, Roelfs, Holen, Lin, Smeland, Andreassen); Psychosis Studies, Institute of Psychiatry, Psychology, and Neurosciences, King’s College London (Hindley); Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo (Frei); INSERM UMR-S1144, Université Paris Cité, Paris (Icick); Department of Cognitive Science (Fan), Multimodal Imaging Laboratory (Fan, Dale), and Departments of Psychiatry, Neurosciences, and Radiology (Dale), University of California, San Diego, La Jolla; Department of Medical Genetics, Oslo University Hospital, Oslo (Djurovic); NORMENT Center, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); KG Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo (Shadrin, Djurovic, Andreassen).
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Notes

Send correspondence to Dr. Hindley ([email protected]).

Competing Interests

Dr. Dale is a founder of and holds equity in Cortechs.ai and serves on its scientific advisory board; he is a member of the scientific advisory boards of HealthLytix and the Mohn Medical Imaging and Visualization Center (Bergen, Norway); and he receives funding through a research agreement between General Electric Healthcare and UCSD. Prof. Andreassen has received speaking honoraria from Lundbeck and has served as a consultant for HealthLytix. The other authors report no financial relationships with commercial interests.

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