TY - JOUR
T1 - A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders
AU - Lombardi, Laura
AU - Le Clerc, Sigrid
AU - Wu, Ching-Lien
AU - Bouassida, Jihène
AU - Boukouaci, Wahid
AU - Sugusabesan, Sobika
AU - Richard, Jean-Romain
AU - Lajnef, Mohamed
AU - Tison, Maxime
AU - Le Corvoisier, Philippe
AU - Barau, Caroline
AU - Banaschewski, Tobias
AU - Holt, Rosemary
AU - Durston, Sarah
AU - Persico, Antonio M
AU - Oakley, Bethany
AU - Loth, Eva
AU - Buitelaar, Jan
AU - Murphy, Declan
AU - Leboyer, Marion
AU - Zagury, Jean-François
AU - Tamouza, Ryad
N1 - Funding Information:
The work was supported by grants from the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programs which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 programs, and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; and by the Horizon2020 supported program CANDY Grant No. 847818). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders (IHI-JU2). The work was further supported by the Fondation FondaMental and the LVMH group. Laura Lombardi benefits from a fellowship no. FDM202006011305 from Fondation de la Recherche Médicale (FRM). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 21/12/2022.
Funding Information:
The work was supported by grants from the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programs which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 programs, and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; and by the Horizon2020 supported program CANDY Grant No. 847818). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders (IHI-JU2). The work was further supported by the Fondation FondaMental and the LVMH group. Laura Lombardi benefits from a fellowship no. FDM202006011305 from Fondation de la Recherche Médicale (FRM). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 21/12/2022.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7/6
Y1 - 2023/7/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85163968865&partnerID=8YFLogxK
U2 - 10.1038/s41398-023-02550-y
DO - 10.1038/s41398-023-02550-y
M3 - Article
C2 - 37407551
SN - 2158-3188
VL - 13
SP - 1
EP - 13
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 244
ER -