Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry

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

doi:10.1016/j.biopsych.2022.08.024

Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Polygenicity and genetic heterogeneity pose great challenges for studying psychiatric conditions. Genetically informed approaches have been implemented in neuroimaging studies to address this issue. However, the effects on functional connectivity of rare and common genetic risks for psychiatric disorders are largely unknown. Our objectives were to estimate and compare the effect sizes on brain connectivity of psychiatric genomic risk factors with various levels of complexity: oligogenic copy number variants (CNVs), multigenic CNVs, and polygenic risk scores (PRSs) as well as idiopathic psychiatric conditions and traits.

METHODS: Resting-state functional magnetic resonance imaging data were processed using the same pipeline across 9 datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRSs, 4 idiopathic psychiatric conditions (1022 individuals with autism, schizophrenia, bipolar conditions, or attention-deficit/hyperactivity disorder), and 2 traits (31,424 unaffected control subjects).

RESULTS: Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2-0.65 z score), followed by psychiatric conditions (0.15-0.42), neuroticism and fluid intelligence (0.02-0.03), and PRSs (0.01-0.02). Effect sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r = 0.9, p = 5.93 × 10-6). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r = -0.88, p = 8.78 × 10-6). PRSs had disproportionately low effect sizes on connectivity compared with CNVs conferring similar risk for disease.

CONCLUSIONS: Heterogeneity and polygenicity affect our ability to detect brain connectivity alterations underlying psychiatric manifestations.

Original language	English
Pages (from-to)	45-58
Number of pages	14
Journal	Biological Psychiatry
Volume	93
Issue number	1
Early online date	2 Sept 2022
DOIs	https://doi.org/10.1016/j.biopsych.2022.08.024
Publication status	Published - 1 Jan 2023

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Moreau, C. A., Harvey, A., Kumar, K., Huguet, G., Urchs, S. G. W., Douard, E. A., Schultz, L. M., Sharmarke, H., Jizi, K., Martin, C.-O., Younis, N., Tamer, P., Rolland, T., Martineau, J.-L., Orban, P., Silva, A. I., Hall, J., van den Bree, M. B. M., Owen, M. J., ... Jacquemont, S. (2023). Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry. Biological Psychiatry, 93(1), 45-58. https://doi.org/10.1016/j.biopsych.2022.08.024

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title = "Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry",

abstract = "BACKGROUND: Polygenicity and genetic heterogeneity pose great challenges for studying psychiatric conditions. Genetically informed approaches have been implemented in neuroimaging studies to address this issue. However, the effects on functional connectivity of rare and common genetic risks for psychiatric disorders are largely unknown. Our objectives were to estimate and compare the effect sizes on brain connectivity of psychiatric genomic risk factors with various levels of complexity: oligogenic copy number variants (CNVs), multigenic CNVs, and polygenic risk scores (PRSs) as well as idiopathic psychiatric conditions and traits.METHODS: Resting-state functional magnetic resonance imaging data were processed using the same pipeline across 9 datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRSs, 4 idiopathic psychiatric conditions (1022 individuals with autism, schizophrenia, bipolar conditions, or attention-deficit/hyperactivity disorder), and 2 traits (31,424 unaffected control subjects).RESULTS: Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2-0.65 z score), followed by psychiatric conditions (0.15-0.42), neuroticism and fluid intelligence (0.02-0.03), and PRSs (0.01-0.02). Effect sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r = 0.9, p = 5.93 × 10-6). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r = -0.88, p = 8.78 × 10-6). PRSs had disproportionately low effect sizes on connectivity compared with CNVs conferring similar risk for disease.CONCLUSIONS: Heterogeneity and polygenicity affect our ability to detect brain connectivity alterations underlying psychiatric manifestations.",

author = "Moreau, {Clara A} and Annabelle Harvey and Kuldeep Kumar and Guillaume Huguet and Urchs, {Sebastian G W} and Douard, {Elise A} and Schultz, {Laura M} and Hanad Sharmarke and Khadije Jizi and Charles-Olivier Martin and Nadine Younis and Petra Tamer and Thomas Rolland and Jean-Louis Martineau and Pierre Orban and Silva, {Ana Isabel} and Jeremy Hall and {van den Bree}, {Marianne B M} and Owen, {Michael J} and Linden, {David E J} and Aurelie Labbe and Sarah Lipp{\'e} and Bearden, {Carrie E} and Laura Almasy and Glahn, {David C} and Thompson, {Paul M} and Thomas Bourgeron and Pierre Bellec and Sebastien Jacquemont",

year = "2023",

month = jan,

day = "1",

doi = "10.1016/j.biopsych.2022.08.024",

language = "English",

volume = "93",

pages = "45--58",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Science",

number = "1",

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Moreau, CA, Harvey, A, Kumar, K, Huguet, G, Urchs, SGW, Douard, EA, Schultz, LM, Sharmarke, H, Jizi, K, Martin, C-O, Younis, N, Tamer, P, Rolland, T, Martineau, J-L, Orban, P, Silva, AI, Hall, J, van den Bree, MBM, Owen, MJ, Linden, DEJ, Labbe, A, Lippé, S, Bearden, CE, Almasy, L, Glahn, DC, Thompson, PM, Bourgeron, T, Bellec, P & Jacquemont, S 2023, 'Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry', Biological Psychiatry, vol. 93, no. 1, pp. 45-58. https://doi.org/10.1016/j.biopsych.2022.08.024

TY - JOUR

T1 - Genetic Heterogeneity Shapes Brain Connectivity in Psychiatry

AU - Moreau, Clara A

AU - Harvey, Annabelle

AU - Kumar, Kuldeep

AU - Huguet, Guillaume

AU - Urchs, Sebastian G W

AU - Douard, Elise A

AU - Schultz, Laura M

AU - Sharmarke, Hanad

AU - Jizi, Khadije

AU - Martin, Charles-Olivier

AU - Younis, Nadine

AU - Tamer, Petra

AU - Rolland, Thomas

AU - Martineau, Jean-Louis

AU - Orban, Pierre

AU - Silva, Ana Isabel

AU - Hall, Jeremy

AU - van den Bree, Marianne B M

AU - Owen, Michael J

AU - Linden, David E J

AU - Labbe, Aurelie

AU - Lippé, Sarah

AU - Bearden, Carrie E

AU - Almasy, Laura

AU - Glahn, David C

AU - Thompson, Paul M

AU - Bourgeron, Thomas

AU - Bellec, Pierre

AU - Jacquemont, Sebastien

PY - 2023/1/1

Y1 - 2023/1/1

N2 - BACKGROUND: Polygenicity and genetic heterogeneity pose great challenges for studying psychiatric conditions. Genetically informed approaches have been implemented in neuroimaging studies to address this issue. However, the effects on functional connectivity of rare and common genetic risks for psychiatric disorders are largely unknown. Our objectives were to estimate and compare the effect sizes on brain connectivity of psychiatric genomic risk factors with various levels of complexity: oligogenic copy number variants (CNVs), multigenic CNVs, and polygenic risk scores (PRSs) as well as idiopathic psychiatric conditions and traits.METHODS: Resting-state functional magnetic resonance imaging data were processed using the same pipeline across 9 datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRSs, 4 idiopathic psychiatric conditions (1022 individuals with autism, schizophrenia, bipolar conditions, or attention-deficit/hyperactivity disorder), and 2 traits (31,424 unaffected control subjects).RESULTS: Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2-0.65 z score), followed by psychiatric conditions (0.15-0.42), neuroticism and fluid intelligence (0.02-0.03), and PRSs (0.01-0.02). Effect sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r = 0.9, p = 5.93 × 10-6). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r = -0.88, p = 8.78 × 10-6). PRSs had disproportionately low effect sizes on connectivity compared with CNVs conferring similar risk for disease.CONCLUSIONS: Heterogeneity and polygenicity affect our ability to detect brain connectivity alterations underlying psychiatric manifestations.

AB - BACKGROUND: Polygenicity and genetic heterogeneity pose great challenges for studying psychiatric conditions. Genetically informed approaches have been implemented in neuroimaging studies to address this issue. However, the effects on functional connectivity of rare and common genetic risks for psychiatric disorders are largely unknown. Our objectives were to estimate and compare the effect sizes on brain connectivity of psychiatric genomic risk factors with various levels of complexity: oligogenic copy number variants (CNVs), multigenic CNVs, and polygenic risk scores (PRSs) as well as idiopathic psychiatric conditions and traits.METHODS: Resting-state functional magnetic resonance imaging data were processed using the same pipeline across 9 datasets. Twenty-nine connectome-wide association studies were performed to characterize the effects of 15 CNVs (1003 carriers), 7 PRSs, 4 idiopathic psychiatric conditions (1022 individuals with autism, schizophrenia, bipolar conditions, or attention-deficit/hyperactivity disorder), and 2 traits (31,424 unaffected control subjects).RESULTS: Effect sizes on connectivity were largest for psychiatric CNVs (estimates: 0.2-0.65 z score), followed by psychiatric conditions (0.15-0.42), neuroticism and fluid intelligence (0.02-0.03), and PRSs (0.01-0.02). Effect sizes of CNVs on connectivity were correlated to their effects on cognition and risk for disease (r = 0.9, p = 5.93 × 10-6). However, effect sizes of CNVs adjusted for the number of genes significantly decreased from small oligogenic to large multigenic CNVs (r = -0.88, p = 8.78 × 10-6). PRSs had disproportionately low effect sizes on connectivity compared with CNVs conferring similar risk for disease.CONCLUSIONS: Heterogeneity and polygenicity affect our ability to detect brain connectivity alterations underlying psychiatric manifestations.

U2 - 10.1016/j.biopsych.2022.08.024

DO - 10.1016/j.biopsych.2022.08.024

M3 - Article

C2 - 36372570

SN - 0006-3223

VL - 93

SP - 45

EP - 58

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 1

ER -