Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderResearch in context
Summary: Background: Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multif...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423003110 |
| _version_ | 1827876819687178240 |
|---|---|
| author | In-Hee Lee Douglas I. Walker Yufei Lin Matthew Ryan Smith Kenneth D. Mandl Dean P. Jones Sek Won Kong |
| author_facet | In-Hee Lee Douglas I. Walker Yufei Lin Matthew Ryan Smith Kenneth D. Mandl Dean P. Jones Sek Won Kong |
| author_sort | In-Hee Lee |
| collection | DOAJ |
| description | Summary: Background: Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members. Methods: We employed an untargeted, high-resolution metabolomics platform to analyse 14,342 features across 1099 plasma samples. These samples were collected from probands and their family members participating in the Autism Genetic Resource Exchange (AGRE) (N = 658), compared with neurotypical individuals enrolled in the PrecisionLink Health Discovery (PLHD) program at Boston Children's Hospital (N = 441). We conducted a metabolite quantitative trait loci (mQTL) analysis using whole-genome genotyping data from each cohort in AGRE and PLHD, aiming to prioritize significant mQTL and metabolite pairs that were exclusively observed in AGRE. Findings: Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P < 5.27 × 10−11), 44 of which were not observed in the PLHD group. Plasma glutamine levels were found to be associated with variants in the NLGN1 gene, a gene that encodes post-synaptic cell-adhesion molecules in excitatory neurons. This association was not detected in the PLHD group. Notably, a significant negative correlation between plasma glutamine and glutamate levels was observed in the AGRE group, but not in the PLHD group. Furthermore, plasma glutamine levels showed a negative correlation with the severity of restrictive and repetitive behaviours (RRB) in ASD, although no direct association was observed between RRB severity and the NLGN1 genotype. Interpretation: Our findings suggest that plasma glutamine levels could potentially serve as an endophenotype, thus establishing a link between the genetic risk associated with NLGN1 and the severity of RRB in ASD. This identified association could facilitate the development of novel therapeutic targets, assist in selecting specific cohorts for clinical trials, and provide insights into target symptoms for future ASD treatment strategies. Funding: This work was supported by the National Institute of Health (grant numbers: R01MH107205, U01TR002623, R24OD024622, OT2OD032720, and R01NS129188) and the PrecisionLink Biobank for Health Discovery at Boston Children’s Hospital. |
| first_indexed | 2024-03-12T17:26:53Z |
| format | Article |
| id | doaj.art-c16ac138231a4ce8923a5cea90341a7e |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-12T17:26:53Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-c16ac138231a4ce8923a5cea90341a7e2023-08-05T05:16:07ZengElsevierEBioMedicine2352-39642023-09-0195104746Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderResearch in contextIn-Hee Lee0Douglas I. Walker1Yufei Lin2Matthew Ryan Smith3Kenneth D. Mandl4Dean P. Jones5Sek Won Kong6Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02215, USAGangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USAComputational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02215, USADivision of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA, 30602, USA; Atlanta Department of Veterans Affairs Medical Center, Decatur, GA, 30033, USAComputational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02215, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USADivision of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA, 30602, USAComputational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA; Corresponding author. 401 Park Drive, LM5528.4, Boston Children's Hospital, Boston, MA, 02215, USA.Summary: Background: Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members. Methods: We employed an untargeted, high-resolution metabolomics platform to analyse 14,342 features across 1099 plasma samples. These samples were collected from probands and their family members participating in the Autism Genetic Resource Exchange (AGRE) (N = 658), compared with neurotypical individuals enrolled in the PrecisionLink Health Discovery (PLHD) program at Boston Children's Hospital (N = 441). We conducted a metabolite quantitative trait loci (mQTL) analysis using whole-genome genotyping data from each cohort in AGRE and PLHD, aiming to prioritize significant mQTL and metabolite pairs that were exclusively observed in AGRE. Findings: Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P < 5.27 × 10−11), 44 of which were not observed in the PLHD group. Plasma glutamine levels were found to be associated with variants in the NLGN1 gene, a gene that encodes post-synaptic cell-adhesion molecules in excitatory neurons. This association was not detected in the PLHD group. Notably, a significant negative correlation between plasma glutamine and glutamate levels was observed in the AGRE group, but not in the PLHD group. Furthermore, plasma glutamine levels showed a negative correlation with the severity of restrictive and repetitive behaviours (RRB) in ASD, although no direct association was observed between RRB severity and the NLGN1 genotype. Interpretation: Our findings suggest that plasma glutamine levels could potentially serve as an endophenotype, thus establishing a link between the genetic risk associated with NLGN1 and the severity of RRB in ASD. This identified association could facilitate the development of novel therapeutic targets, assist in selecting specific cohorts for clinical trials, and provide insights into target symptoms for future ASD treatment strategies. Funding: This work was supported by the National Institute of Health (grant numbers: R01MH107205, U01TR002623, R24OD024622, OT2OD032720, and R01NS129188) and the PrecisionLink Biobank for Health Discovery at Boston Children’s Hospital.http://www.sciencedirect.com/science/article/pii/S2352396423003110Autism spectrum disorderEndophenotypeGlutamineNeuroligin-1Glutamine-glutamate cycleExcitatory-inhibitory imbalance |
| spellingShingle | In-Hee Lee Douglas I. Walker Yufei Lin Matthew Ryan Smith Kenneth D. Mandl Dean P. Jones Sek Won Kong Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderResearch in context EBioMedicine Autism spectrum disorder Endophenotype Glutamine Neuroligin-1 Glutamine-glutamate cycle Excitatory-inhibitory imbalance |
| title | Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderResearch in context |
| title_full | Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderResearch in context |
| title_fullStr | Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderResearch in context |
| title_full_unstemmed | Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderResearch in context |
| title_short | Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderResearch in context |
| title_sort | association between neuroligin 1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorderresearch in context |
| topic | Autism spectrum disorder Endophenotype Glutamine Neuroligin-1 Glutamine-glutamate cycle Excitatory-inhibitory imbalance |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423003110 |
| work_keys_str_mv | AT inheelee associationbetweenneuroligin1polymorphismandplasmaglutaminelevelsinindividualswithautismspectrumdisorderresearchincontext AT douglasiwalker associationbetweenneuroligin1polymorphismandplasmaglutaminelevelsinindividualswithautismspectrumdisorderresearchincontext AT yufeilin associationbetweenneuroligin1polymorphismandplasmaglutaminelevelsinindividualswithautismspectrumdisorderresearchincontext AT matthewryansmith associationbetweenneuroligin1polymorphismandplasmaglutaminelevelsinindividualswithautismspectrumdisorderresearchincontext AT kennethdmandl associationbetweenneuroligin1polymorphismandplasmaglutaminelevelsinindividualswithautismspectrumdisorderresearchincontext AT deanpjones associationbetweenneuroligin1polymorphismandplasmaglutaminelevelsinindividualswithautismspectrumdisorderresearchincontext AT sekwonkong associationbetweenneuroligin1polymorphismandplasmaglutaminelevelsinindividualswithautismspectrumdisorderresearchincontext |