Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study
Abstract Background Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing diso...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-023-02920-9 |
| _version_ | 1797452371872186368 |
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| author | Nanyu Kuang Zhaowen Liu Gechang Yu Xinran Wu Benjamin Becker Huaxin Fan Songjun Peng Kai Zhang Jiajia Zhao Jujiao Kang Guiying Dong Xingming Zhao Barbara J. Sahakian Trevor W. Robbins Wei Cheng Jianfeng Feng Gunter Schumann Lena Palaniyappan Jie Zhang |
| author_facet | Nanyu Kuang Zhaowen Liu Gechang Yu Xinran Wu Benjamin Becker Huaxin Fan Songjun Peng Kai Zhang Jiajia Zhao Jujiao Kang Guiying Dong Xingming Zhao Barbara J. Sahakian Trevor W. Robbins Wei Cheng Jianfeng Feng Gunter Schumann Lena Palaniyappan Jie Zhang |
| author_sort | Nanyu Kuang |
| collection | DOAJ |
| description | Abstract Background Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical differences represent a simple aggregate of the effects on each disorder and if these comorbidity-associated cortical surface differences relate to a distinct genetic underpinning. Methods We studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9–10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (dysthymia, major depressive disorder, disruptive mood dysregulation disorder, agoraphobia, panic disorder, specific phobia, separation anxiety disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder), externalizing (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder) diagnostic groups, a group with comorbidity of the two and a healthy control group. Genome-wide association analysis (GWAS) and cell type specificity analysis were performed on 4468 unrelated European participants from this cohort. Results Smaller cortical surface area but higher thickness was noted across patient groups when compared to controls. Children with comorbid internalizing and externalizing disorders had more pronounced areal reduction than those without comorbidity, indicating an additive burden. In contrast, cortical thickness had a non-linear effect with comorbidity: the comorbid group had no significant CT differences, while those patient groups without comorbidity had significantly higher thickness compare to healthy controls. Distinct biological pathways were implicated in regional SA and CT differences. Specifically, CT differences were associated with immune-related processes implicating astrocytes and oligodendrocytes, while SA-related differences related mainly to inhibitory neurons. Conclusion The emergence of comorbidity across distinct clusters of psychopathology is unlikely to be due to a simple additive neurobiological effect alone. Distinct developmental risk moderated by immune-related adaptation processes, with unique genetic and cell-specific factors, may contribute to underlying SA and CT differences. Children with the highest risk but lowest resilience, both captured in their developmental morphometry, may develop a comorbid illness pattern. |
| first_indexed | 2024-03-09T15:08:08Z |
| format | Article |
| id | doaj.art-b154f869045b4c3bb8ccfbfe491e818b |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-03-09T15:08:08Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-b154f869045b4c3bb8ccfbfe491e818b2023-11-26T13:34:14ZengBMCBMC Medicine1741-70152023-08-0121111710.1186/s12916-023-02920-9Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric studyNanyu Kuang0Zhaowen Liu1Gechang Yu2Xinran Wu3Benjamin Becker4Huaxin Fan5Songjun Peng6Kai Zhang7Jiajia Zhao8Jujiao Kang9Guiying Dong10Xingming Zhao11Barbara J. Sahakian12Trevor W. Robbins13Wei Cheng14Jianfeng Feng15Gunter Schumann16Lena Palaniyappan17Jie Zhang18Institute of Science and Technology for Brain Inspired Intelligence, Fudan UniversitySchool of Computer Science, Northwestern Polytechnical UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityClinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of ChinaInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Computer Science and Technology, East China Normal UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityDouglas Mental Health University Institute, Department of Psychiatry, McGill UniversityInstitute of Science and Technology for Brain Inspired Intelligence, Fudan UniversityAbstract Background Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical differences represent a simple aggregate of the effects on each disorder and if these comorbidity-associated cortical surface differences relate to a distinct genetic underpinning. Methods We studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9–10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (dysthymia, major depressive disorder, disruptive mood dysregulation disorder, agoraphobia, panic disorder, specific phobia, separation anxiety disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder), externalizing (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder) diagnostic groups, a group with comorbidity of the two and a healthy control group. Genome-wide association analysis (GWAS) and cell type specificity analysis were performed on 4468 unrelated European participants from this cohort. Results Smaller cortical surface area but higher thickness was noted across patient groups when compared to controls. Children with comorbid internalizing and externalizing disorders had more pronounced areal reduction than those without comorbidity, indicating an additive burden. In contrast, cortical thickness had a non-linear effect with comorbidity: the comorbid group had no significant CT differences, while those patient groups without comorbidity had significantly higher thickness compare to healthy controls. Distinct biological pathways were implicated in regional SA and CT differences. Specifically, CT differences were associated with immune-related processes implicating astrocytes and oligodendrocytes, while SA-related differences related mainly to inhibitory neurons. Conclusion The emergence of comorbidity across distinct clusters of psychopathology is unlikely to be due to a simple additive neurobiological effect alone. Distinct developmental risk moderated by immune-related adaptation processes, with unique genetic and cell-specific factors, may contribute to underlying SA and CT differences. Children with the highest risk but lowest resilience, both captured in their developmental morphometry, may develop a comorbid illness pattern.https://doi.org/10.1186/s12916-023-02920-9Cortical surface areaThicknessDevelopmentalResilienceGWAS |
| spellingShingle | Nanyu Kuang Zhaowen Liu Gechang Yu Xinran Wu Benjamin Becker Huaxin Fan Songjun Peng Kai Zhang Jiajia Zhao Jujiao Kang Guiying Dong Xingming Zhao Barbara J. Sahakian Trevor W. Robbins Wei Cheng Jianfeng Feng Gunter Schumann Lena Palaniyappan Jie Zhang Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study BMC Medicine Cortical surface area Thickness Developmental Resilience GWAS |
| title | Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study |
| title_full | Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study |
| title_fullStr | Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study |
| title_full_unstemmed | Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study |
| title_short | Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study |
| title_sort | neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders genomics and cell specific expression enriched morphometric study |
| topic | Cortical surface area Thickness Developmental Resilience GWAS |
| url | https://doi.org/10.1186/s12916-023-02920-9 |
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