Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Author:

Moreau Clara A123ORCID,Kumar Kuldeep2,Harvey Annabelle23,Huguet Guillaume2,Urchs Sebastian G W34,Schultz Laura M5,Sharmarke Hanad3,Jizi Khadije2,Martin Charles-Olivier2,Younis Nadine2,Tamer Petra2,Martineau Jean-Louis2,Orban Pierre67,Silva Ana Isabel8910,Hall Jeremy89,van den Bree Marianne B M89,Owen Michael J89ORCID,Linden David E J910,Lippé Sarah2,Bearden Carrie E111213ORCID,Almasy Laura51415,Glahn David C1617,Thompson Paul M18,Bourgeron Thomas1,Bellec Pierre3,Jacquemont Sebastien2ORCID

Affiliation:

1. Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université Paris Cité , Paris , France

2. Sainte Justine Research Center, University of Montréal , Montréal, QC H3T 1C5 , Canada

3. Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal, UdeM , Montreal, QC H3W 1W5 , Canada

4. Montreal Neurological Institute, McGill University , Montreal, QC H3A 2B4 , Canada

5. Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia , Philadelphia, PA , USA

6. Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal, UdeM , Montréal, QC H1N 3V2 , Canada

7. Département de Psychiatrie et d’Addictologie, Université de Montréal, Pavillon Roger-Gaudry, C.P. 6128, Succursale Centre-ville , Montréal, QC H3C 3J7 , Canada

8. Neuroscience and Mental Health Research Institute, Cardiff University , Cardiff , UK

9. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University , Cardiff , UK

10. School for Mental Health and Neuroscience, Maastricht University , Maastricht , The Netherlands

11. Integrative Center for Neurogenetics, Semel Institute for Neuroscience and Human Behavior , Los Angeles, CA 90095 , USA

12. Department of Psychiatry, University of California, Los Angeles , Los Angeles, CA 90095 , USA

13. Department of Biobehavioral Sciences and Psychology, University of California, Los Angeles , Los Angeles, CA 90095 , USA

14. Department of Genetics, University of Pennsylvania , Philadelphia, PA , USA

15. Lifespan Brain Institute, Children's Hospital of Philadelphia , Philadelphia, PA , USA

16. Department of Psychiatry, Harvard Medical School , Cambridge, MA 02115 , USA

17. Boston Children’s Hospital, Tommy Fuss Center for Neuropsychiatric Disease Research , 300 Longwood Avenue, Boston, MA 02115 , USA

18. Imaging Genetics Center, Stevens Institute for Neuroimaging and Informatics, Keck USC School of Medicine , Marina del Rey, CA , USA

Abstract

Abstract Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic—rFunctional connectivity = 0.71 [0.40–0.87] and rTranscriptomic—rFunctional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms—amenable to intervention—across psychiatric conditions and genetic risks.

Funder

Compute Canada

Canada First Research Excellence Fund

Institute of Data Valorization

Healthy Brain Healthy Lives

Jeanne et Jean Louis Levesque Foundation

Brain Canada Multi-Investigator initiative

The Canadian Institutes of Health Research

Wellcome Trust

National Centre for Mental Health

Health and Care Research Wales

SNF

NIH

Consortium for Neuropsychiatric Phenomics

Medical Research

Courtois foundation

Simons Foundation

U.S. NIH

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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