Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth
Abstract Background Increased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated...
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | Genome Biology |
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| Online Access: | https://doi.org/10.1186/s13059-023-02878-0 |
| _version_ | 1797864547691790336 |
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| author | Leanna M. Hernandez Minsoo Kim Pan Zhang Richard A. I. Bethlehem Gil Hoftman Robert Loughnan Diana Smith Susan Y. Bookheimer Chun Chieh Fan Carrie E. Bearden Wesley K. Thompson Michael J. Gandal |
| author_facet | Leanna M. Hernandez Minsoo Kim Pan Zhang Richard A. I. Bethlehem Gil Hoftman Robert Loughnan Diana Smith Susan Y. Bookheimer Chun Chieh Fan Carrie E. Bearden Wesley K. Thompson Michael J. Gandal |
| author_sort | Leanna M. Hernandez |
| collection | DOAJ |
| description | Abstract Background Increased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated with the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 children aged 9–12 years to examine the relationship between genetically regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms. Results While C4A GREx is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9–10 years predicts a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia. Conclusions Our results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset. |
| first_indexed | 2024-04-09T22:53:41Z |
| format | Article |
| id | doaj.art-3265b006624a49fb975cf0256fe1af0e |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-04-09T22:53:41Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-3265b006624a49fb975cf0256fe1af0e2023-03-22T11:22:19ZengBMCGenome Biology1474-760X2023-03-0124111910.1186/s13059-023-02878-0Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youthLeanna M. Hernandez0Minsoo Kim1Pan Zhang2Richard A. I. Bethlehem3Gil Hoftman4Robert Loughnan5Diana Smith6Susan Y. Bookheimer7Chun Chieh Fan8Carrie E. Bearden9Wesley K. Thompson10Michael J. Gandal11Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los AngelesDepartment of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los AngelesDepartment of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los AngelesUniversity of Cambridge, Department of Psychiatry, Cambridge Biomedical CampusDepartment of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los AngelesPopulation Neuroscience and Genetics Lab, University of California, San DiegoPopulation Neuroscience and Genetics Lab, University of California, San DiegoDepartment of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los AngelesPopulation Neuroscience and Genetics Lab, University of California, San DiegoDepartment of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los AngelesPopulation Neuroscience and Genetics Lab, University of California, San DiegoDepartment of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los AngelesAbstract Background Increased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated with the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 children aged 9–12 years to examine the relationship between genetically regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms. Results While C4A GREx is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9–10 years predicts a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia. Conclusions Our results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset.https://doi.org/10.1186/s13059-023-02878-0SchizophreniaPsychosisNeuroimagingGeneticsGene expressionComplement |
| spellingShingle | Leanna M. Hernandez Minsoo Kim Pan Zhang Richard A. I. Bethlehem Gil Hoftman Robert Loughnan Diana Smith Susan Y. Bookheimer Chun Chieh Fan Carrie E. Bearden Wesley K. Thompson Michael J. Gandal Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth Genome Biology Schizophrenia Psychosis Neuroimaging Genetics Gene expression Complement |
| title | Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth |
| title_full | Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth |
| title_fullStr | Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth |
| title_full_unstemmed | Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth |
| title_short | Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth |
| title_sort | multi ancestry phenome wide association of complement component 4 variation with psychiatric and brain phenotypes in youth |
| topic | Schizophrenia Psychosis Neuroimaging Genetics Gene expression Complement |
| url | https://doi.org/10.1186/s13059-023-02878-0 |
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