Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Clara A Moreau; Kuldeep Kumar; Annabelle Harvey; Guillaume Huguet; Sebastian G W Urchs; Laura M Schultz; Hanad Sharmarke; Khadije Jizi; Charles-Olivier Martin; Nadine Younis; Petra Tamer; Jean-Louis Martineau; Pierre Orban; Ana Isabel Silva; Jeremy Hall; Marianne B M van den Bree; Michael J Owen; David E J Linden; Sarah Lippé; Carrie E Bearden; Laura Almasy; David C Glahn; Paul M Thompson; Thomas Bourgeron; Pierre Bellec; Sebastien Jacquemont

doi:10.1093/brain/awac315

Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Brain. 2023 Apr 19;146(4):1686-1696. doi: 10.1093/brain/awac315.

Authors

Clara A Moreau^{1

2

3}, Kuldeep Kumar², Annabelle Harvey^{2

3}, Guillaume Huguet², Sebastian G W Urchs^{3

4}, Laura M Schultz⁵, Hanad Sharmarke³, Khadije Jizi², Charles-Olivier Martin², Nadine Younis², Petra Tamer², Jean-Louis Martineau², Pierre Orban^{6

7}, Ana Isabel Silva^{8

9

10}, Jeremy Hall^{8

9}, Marianne B M van den Bree^{8

9}, Michael J Owen^{8

9}, David E J Linden^{9

10}, Sarah Lippé², Carrie E Bearden^{11

12

13}, Laura Almasy^{5

14

15}, David C Glahn^{16

17}, Paul M Thompson¹⁸, Thomas Bourgeron¹, Pierre Bellec³, Sebastien Jacquemont²

Affiliations

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

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.

Keywords: autism spectrum disorder; copy-number variant; functional connectivity; pleiotropy; psychiatry.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain / diagnostic imaging
Connectome*
Genetic Pleiotropy
Humans
Magnetic Resonance Imaging
Mental Disorders* / diagnostic imaging
Mental Disorders* / genetics

Abstract

Publication types

MeSH terms

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