A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders
Abstract Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-023-02550-y |
| _version_ | 1827905225120284672 |
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| author | Laura Lombardi Sigrid Le Clerc Ching-Lien Wu Jihène Bouassida Wahid Boukouaci Sobika Sugusabesan Jean-Romain Richard Mohamed Lajnef Maxime Tison Philippe Le Corvoisier Caroline Barau Tobias Banaschewski Rosemary Holt Sarah Durston Antonio M. Persico Bethany Oakley Eva Loth Jan Buitelaar Declan Murphy Marion Leboyer Jean-François Zagury Ryad Tamouza |
| author_facet | Laura Lombardi Sigrid Le Clerc Ching-Lien Wu Jihène Bouassida Wahid Boukouaci Sobika Sugusabesan Jean-Romain Richard Mohamed Lajnef Maxime Tison Philippe Le Corvoisier Caroline Barau Tobias Banaschewski Rosemary Holt Sarah Durston Antonio M. Persico Bethany Oakley Eva Loth Jan Buitelaar Declan Murphy Marion Leboyer Jean-François Zagury Ryad Tamouza |
| author_sort | Laura Lombardi |
| collection | DOAJ |
| description | Abstract Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (HLA) has been implicated in ASD risk, although seldom investigated. By utilizing a GWAS performed by the EU-AIMS consortium (LEAP cohort), we compared HLA and MHC genetic variants, single nucleotide polymorphisms (SNP), and haplotypes in ASD individuals, versus typically developing controls. We uncovered six SNPs, namely rs9268528, rs9268542, rs9268556, rs14004, rs9268557, and rs8084 that crossed the Bonferroni threshold, which form the underpinnings of 3 independent genetic pathways/blocks that differentially associate with ASD. Block 1 (rs9268528-G, rs9268542-G, rs9268556-C, and rs14004-A) afforded protection against ASD development, whilst the two remaining blocks, namely rs9268557-T, and rs8084-A, associated with heightened risk. rs8084 and rs14004 mapped to the HLA‐DRA gene, whilst the four other SNPs located in the BTNL2 locus. Different combinations amongst BTNL2 SNPs and HLA amino acid variants or classical alleles were found either to afford protection from or contribute to ASD risk, indicating a genetic interplay between BTNL2 and HLA. Interestingly, the detected variants had transcriptional and/or quantitative traits loci implications. As BTNL2 modulates gastrointestinal homeostasis and the identified HLA alleles regulate the gastrointestinal tract in celiac disease, it is proposed that the data on ASD risk may be linked to genetically regulated gut inflammatory processes. These findings might have implications for the prevention and treatment of ASD, via the targeting of gut-related processes. |
| first_indexed | 2024-03-13T00:39:56Z |
| format | Article |
| id | doaj.art-ae3e3409be1844129fafe8a901016542 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-03-13T00:39:56Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-ae3e3409be1844129fafe8a9010165422023-07-09T11:25:47ZengNature Publishing GroupTranslational Psychiatry2158-31882023-07-0113111310.1038/s41398-023-02550-yA human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disordersLaura Lombardi0Sigrid Le Clerc1Ching-Lien Wu2Jihène Bouassida3Wahid Boukouaci4Sobika Sugusabesan5Jean-Romain Richard6Mohamed Lajnef7Maxime Tison8Philippe Le Corvoisier9Caroline Barau10Tobias Banaschewski11Rosemary Holt12Sarah Durston13Antonio M. Persico14Bethany Oakley15Eva Loth16Jan Buitelaar17Declan Murphy18Marion Leboyer19Jean-François Zagury20Ryad Tamouza21Université Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleLaboratoire Génomique, Bio-informatique et Chimie Moléculaire (EA7528), Conservatoire National des Arts et MétiersUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleUniversité Paris Est Créteil, Inserm, Centre Investigation Clinique, CIC 1430, Henri MondorPlateforme de Ressources Biologiques, HU Henri MondorChild and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of HeidelbergAutism Research Centre, Department of Psychiatry, University of CambridgeEducation Center, University Medical Center UtrechtChild and Adolescent Neuropsychiatry Program at Modena University Hospital, & Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio EmiliaDepartment of Forensic and Neurodevelopemental Science, Institute of Psychatry, Psychology and Neuroscience, King’s College LondonDepartment of Forensic and Neurodevelopemental Science, Institute of Psychatry, Psychology and Neuroscience, King’s College LondonDepartment of Cognitive Neuroscience, Donders Institute for Brain, Cognition and BehaviourDepartment of Forensic and Neurodevelopemental Science, Institute of Psychatry, Psychology and Neuroscience, King’s College LondonUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleLaboratoire Génomique, Bio-informatique et Chimie Moléculaire (EA7528), Conservatoire National des Arts et MétiersUniversité Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelleAbstract Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (HLA) has been implicated in ASD risk, although seldom investigated. By utilizing a GWAS performed by the EU-AIMS consortium (LEAP cohort), we compared HLA and MHC genetic variants, single nucleotide polymorphisms (SNP), and haplotypes in ASD individuals, versus typically developing controls. We uncovered six SNPs, namely rs9268528, rs9268542, rs9268556, rs14004, rs9268557, and rs8084 that crossed the Bonferroni threshold, which form the underpinnings of 3 independent genetic pathways/blocks that differentially associate with ASD. Block 1 (rs9268528-G, rs9268542-G, rs9268556-C, and rs14004-A) afforded protection against ASD development, whilst the two remaining blocks, namely rs9268557-T, and rs8084-A, associated with heightened risk. rs8084 and rs14004 mapped to the HLA‐DRA gene, whilst the four other SNPs located in the BTNL2 locus. Different combinations amongst BTNL2 SNPs and HLA amino acid variants or classical alleles were found either to afford protection from or contribute to ASD risk, indicating a genetic interplay between BTNL2 and HLA. Interestingly, the detected variants had transcriptional and/or quantitative traits loci implications. As BTNL2 modulates gastrointestinal homeostasis and the identified HLA alleles regulate the gastrointestinal tract in celiac disease, it is proposed that the data on ASD risk may be linked to genetically regulated gut inflammatory processes. These findings might have implications for the prevention and treatment of ASD, via the targeting of gut-related processes.https://doi.org/10.1038/s41398-023-02550-y |
| spellingShingle | Laura Lombardi Sigrid Le Clerc Ching-Lien Wu Jihène Bouassida Wahid Boukouaci Sobika Sugusabesan Jean-Romain Richard Mohamed Lajnef Maxime Tison Philippe Le Corvoisier Caroline Barau Tobias Banaschewski Rosemary Holt Sarah Durston Antonio M. Persico Bethany Oakley Eva Loth Jan Buitelaar Declan Murphy Marion Leboyer Jean-François Zagury Ryad Tamouza A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders Translational Psychiatry |
| title | A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders |
| title_full | A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders |
| title_fullStr | A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders |
| title_full_unstemmed | A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders |
| title_short | A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders |
| title_sort | human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders |
| url | https://doi.org/10.1038/s41398-023-02550-y |
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