한빛사논문
- 조회631
In-Hee Lee a, Douglas I. Walker b, Yufei Lin a, Matthew Ryan Smith c,d, Kenneth D. Mandl a,e,f, Dean P. Jones c, Sek Won Kong a,f
aComputational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02215, USA
bGangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
cDivision of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA, 30602, USA
dAtlanta Department of Veterans Affairs Medical Center, Decatur, GA, 30033, USA
eDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA
fDepartment of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
Corresponding author: Sek Won Kong
Abstract
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.
논문정보
- Research article
- 2023년 09월 (BRIC 등록일 2023-08-22)
- 국외 연구진
- 의약학 > 유전 및 유전체의학
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