Effect of schizophrenia common variants on infant brain volumes: cross-sectional study in 207 term neonates in developing Human Connectome Project

Hai Le; Konstantina Dimitrakopoulou; Hamel Patel; Charles Curtis; Lucilio Cordero-Grande; David Edwards; Jo Hajnal; Jacques-Donald Tournier; Maria Deprez; Harriet Cullen

doi:10.1038/s41398-023-02413-6

Effect of schizophrenia common variants on infant brain volumes: cross-sectional study in 207 term neonates in developing Human Connectome Project

Hai Le^*, Konstantina Dimitrakopoulou, Hamel Patel, Charles Curtis, Lucilio Cordero-Grande, David Edwards, Jo Hajnal, Jacques-Donald Tournier, Maria Deprez, Harriet Cullen

^*Corresponding author for this work

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Abstract

Increasing lines of evidence suggest deviations from the normal early developmental trajectory could give rise to the onset of schizophrenia during adolescence and young adulthood, but few studies have investigated brain imaging changes associated with schizophrenia common variants in neonates. This study compared the brain volumes of both grey and white matter regions with schizophrenia polygenic risk scores (PRS) for 207 healthy term-born infants of European ancestry. Linear regression was used to estimate the relationship between PRS and brain volumes, with gestational age at birth, postmenstrual age at scan, ancestral principal components, sex and intracranial volumes as covariates. The schizophrenia PRS were negatively associated with the grey (β = -0.08, p = 4.2 × 10-3) and white (β = -0.13, p = 9.4 × 10-3) matter superior temporal gyrus volumes, white frontal lobe volume (β = -0.09, p = 1.5 × 10-3) and the total white matter volume (β = -0.062, p = 1.66 × 10-2). This result also remained robust when incorporating individuals of Asian ancestry. Explorative functional analysis of the schizophrenia risk variants associated with the right frontal lobe white matter volume found enrichment in neurodevelopmental pathways. This preliminary result suggests possible involvement of schizophrenia risk genes in early brain growth, and potential early life structural alterations long before the average age of onset of the disease.

Original language	English
Article number	121
Pages (from-to)	121
Number of pages	1
Journal	Translational psychiatry
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41398-023-02413-6
Publication status	Published - 10 Apr 2023

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PRS_ManuscriptAccepted author manuscript, 851 KBLicence: CC BY

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Le, H., Dimitrakopoulou, K., Patel, H., Curtis, C., Cordero-Grande, L., Edwards, D., Hajnal, J., Tournier, J.-D., Deprez, M., & Cullen, H. (2023). Effect of schizophrenia common variants on infant brain volumes: cross-sectional study in 207 term neonates in developing Human Connectome Project. Translational psychiatry, 13(1), 121. Article 121. https://doi.org/10.1038/s41398-023-02413-6

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title = "Effect of schizophrenia common variants on infant brain volumes: cross-sectional study in 207 term neonates in developing Human Connectome Project",

abstract = "Increasing lines of evidence suggest deviations from the normal early developmental trajectory could give rise to the onset of schizophrenia during adolescence and young adulthood, but few studies have investigated brain imaging changes associated with schizophrenia common variants in neonates. This study compared the brain volumes of both grey and white matter regions with schizophrenia polygenic risk scores (PRS) for 207 healthy term-born infants of European ancestry. Linear regression was used to estimate the relationship between PRS and brain volumes, with gestational age at birth, postmenstrual age at scan, ancestral principal components, sex and intracranial volumes as covariates. The schizophrenia PRS were negatively associated with the grey (β = -0.08, p = 4.2 × 10-3) and white (β = -0.13, p = 9.4 × 10-3) matter superior temporal gyrus volumes, white frontal lobe volume (β = -0.09, p = 1.5 × 10-3) and the total white matter volume (β = -0.062, p = 1.66 × 10-2). This result also remained robust when incorporating individuals of Asian ancestry. Explorative functional analysis of the schizophrenia risk variants associated with the right frontal lobe white matter volume found enrichment in neurodevelopmental pathways. This preliminary result suggests possible involvement of schizophrenia risk genes in early brain growth, and potential early life structural alterations long before the average age of onset of the disease.",

author = "Hai Le and Konstantina Dimitrakopoulou and Hamel Patel and Charles Curtis and Lucilio Cordero-Grande and David Edwards and Jo Hajnal and Jacques-Donald Tournier and Maria Deprez and Harriet Cullen",

note = "Funding Information: Data were provided by the developing Human Connectome Project, KCL-Imperial-Oxford Consortium and the work was funded by ERC grant agreement no. 319456, the Wellcome EPSRC Centre for Medical Engineering at Kings College London (WT 203148/Z/16/Z) and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We are grateful to the families who generously supported this trial. HL is supported by the UK Medical Research Council (MR/N013700/1) and King{\textquoteright}s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences. H.C. is an academic clinical lecturer in Clinical Genetics at Kings College London and is supported by the NIHR. L.C.-G. received support from the Comunidad de Madrid-Spain Support for R&D Projects [BGP18/00178]. The authors acknowledge use of the research computing facility at King{\textquoteright}s College London, Rosalind ( https://rosalind.kcl.ac.uk ). Funding Information: Data were provided by the developing Human Connectome Project, KCL-Imperial-Oxford Consortium and the work was funded by ERC grant agreement no. 319456, the Wellcome EPSRC Centre for Medical Engineering at Kings College London (WT 203148/Z/16/Z) and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We are grateful to the families who generously supported this trial. HL is supported by the UK Medical Research Council (MR/N013700/1) and King{\textquoteright}s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences. H.C. is an academic clinical lecturer in Clinical Genetics at Kings College London and is supported by the NIHR. L.C.-G. received support from the Comunidad de Madrid-Spain Support for R&D Projects [BGP18/00178]. The authors acknowledge use of the research computing facility at King{\textquoteright}s College London, Rosalind (https://rosalind.kcl.ac.uk). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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month = apr,

day = "10",

doi = "10.1038/s41398-023-02413-6",

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Le, H, Dimitrakopoulou, K, Patel, H , Curtis, C , Cordero-Grande, L , Edwards, D , Hajnal, J , Tournier, J-D , Deprez, M & Cullen, H 2023, 'Effect of schizophrenia common variants on infant brain volumes: cross-sectional study in 207 term neonates in developing Human Connectome Project', Translational psychiatry, vol. 13, no. 1, 121, pp. 121. https://doi.org/10.1038/s41398-023-02413-6

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T1 - Effect of schizophrenia common variants on infant brain volumes: cross-sectional study in 207 term neonates in developing Human Connectome Project

AU - Le, Hai

AU - Dimitrakopoulou, Konstantina

AU - Patel, Hamel

AU - Curtis, Charles

AU - Cordero-Grande, Lucilio

AU - Edwards, David

AU - Hajnal, Jo

AU - Tournier, Jacques-Donald

AU - Deprez, Maria

AU - Cullen, Harriet

N1 - Funding Information: Data were provided by the developing Human Connectome Project, KCL-Imperial-Oxford Consortium and the work was funded by ERC grant agreement no. 319456, the Wellcome EPSRC Centre for Medical Engineering at Kings College London (WT 203148/Z/16/Z) and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We are grateful to the families who generously supported this trial. HL is supported by the UK Medical Research Council (MR/N013700/1) and King’s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences. H.C. is an academic clinical lecturer in Clinical Genetics at Kings College London and is supported by the NIHR. L.C.-G. received support from the Comunidad de Madrid-Spain Support for R&D Projects [BGP18/00178]. The authors acknowledge use of the research computing facility at King’s College London, Rosalind ( https://rosalind.kcl.ac.uk ). Funding Information: Data were provided by the developing Human Connectome Project, KCL-Imperial-Oxford Consortium and the work was funded by ERC grant agreement no. 319456, the Wellcome EPSRC Centre for Medical Engineering at Kings College London (WT 203148/Z/16/Z) and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We are grateful to the families who generously supported this trial. HL is supported by the UK Medical Research Council (MR/N013700/1) and King’s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences. H.C. is an academic clinical lecturer in Clinical Genetics at Kings College London and is supported by the NIHR. L.C.-G. received support from the Comunidad de Madrid-Spain Support for R&D Projects [BGP18/00178]. The authors acknowledge use of the research computing facility at King’s College London, Rosalind (https://rosalind.kcl.ac.uk). Publisher Copyright: © 2023, The Author(s).

PY - 2023/4/10

Y1 - 2023/4/10

N2 - Increasing lines of evidence suggest deviations from the normal early developmental trajectory could give rise to the onset of schizophrenia during adolescence and young adulthood, but few studies have investigated brain imaging changes associated with schizophrenia common variants in neonates. This study compared the brain volumes of both grey and white matter regions with schizophrenia polygenic risk scores (PRS) for 207 healthy term-born infants of European ancestry. Linear regression was used to estimate the relationship between PRS and brain volumes, with gestational age at birth, postmenstrual age at scan, ancestral principal components, sex and intracranial volumes as covariates. The schizophrenia PRS were negatively associated with the grey (β = -0.08, p = 4.2 × 10-3) and white (β = -0.13, p = 9.4 × 10-3) matter superior temporal gyrus volumes, white frontal lobe volume (β = -0.09, p = 1.5 × 10-3) and the total white matter volume (β = -0.062, p = 1.66 × 10-2). This result also remained robust when incorporating individuals of Asian ancestry. Explorative functional analysis of the schizophrenia risk variants associated with the right frontal lobe white matter volume found enrichment in neurodevelopmental pathways. This preliminary result suggests possible involvement of schizophrenia risk genes in early brain growth, and potential early life structural alterations long before the average age of onset of the disease.

AB - Increasing lines of evidence suggest deviations from the normal early developmental trajectory could give rise to the onset of schizophrenia during adolescence and young adulthood, but few studies have investigated brain imaging changes associated with schizophrenia common variants in neonates. This study compared the brain volumes of both grey and white matter regions with schizophrenia polygenic risk scores (PRS) for 207 healthy term-born infants of European ancestry. Linear regression was used to estimate the relationship between PRS and brain volumes, with gestational age at birth, postmenstrual age at scan, ancestral principal components, sex and intracranial volumes as covariates. The schizophrenia PRS were negatively associated with the grey (β = -0.08, p = 4.2 × 10-3) and white (β = -0.13, p = 9.4 × 10-3) matter superior temporal gyrus volumes, white frontal lobe volume (β = -0.09, p = 1.5 × 10-3) and the total white matter volume (β = -0.062, p = 1.66 × 10-2). This result also remained robust when incorporating individuals of Asian ancestry. Explorative functional analysis of the schizophrenia risk variants associated with the right frontal lobe white matter volume found enrichment in neurodevelopmental pathways. This preliminary result suggests possible involvement of schizophrenia risk genes in early brain growth, and potential early life structural alterations long before the average age of onset of the disease.

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JO - Translational psychiatry

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ER -

Effect of schizophrenia common variants on infant brain volumes: cross-sectional study in 207 term neonates in developing Human Connectome Project

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