Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02215, USA.
Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.
EBioMedicine. 2023 Sep;95:104746. doi: 10.1016/j.ebiom.2023.104746. Epub 2023 Aug 4.
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.
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.
Within the AGRE group, we identified 54 significant associations between genotypes and metabolite levels (P < 5.27 × 10), 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.
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.
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.
阐明候选基因与自闭症谱系障碍（ASD）表型之间的关系仍然是一个悬而未决的挑战。内表型定义为可遗传的、可测量的定量特征，可能为遗传风险因素与多方面 ASD 表型之间提供中间联系。在这项研究中，我们试图确定 ASD 患者及其家庭成员的血浆代谢物水平是否可以作为内表型。
我们使用无靶向、高分辨率代谢组学平台分析了来自 1099 个血浆样本的 14342 个特征。这些样本来自参与自闭症基因资源交换（AGRE）的先证者及其家庭成员（N=658），并与波士顿儿童医院 PrecisionLink Health Discovery（PLHD）计划中纳入的神经典型个体（N=441）进行比较。我们使用 AGRE 和 PLHD 中每个队列的全基因组基因分型数据进行代谢物数量性状基因座（mQTL）分析，旨在优先确定仅在 AGRE 中观察到的显著 mQTL 和代谢物对。
在 AGRE 组中，我们发现 54 个基因型与代谢物水平之间存在显著关联（P<5.27×10），其中 44 个在 PLHD 组中未观察到。发现血浆谷氨酰胺水平与兴奋性神经元突触后细胞粘附分子 NLGN1 基因的变异有关。在 PLHD 组中未检测到这种关联。值得注意的是，在 AGRE 组中观察到血浆谷氨酰胺与谷氨酸水平之间存在显著负相关，但在 PLHD 组中未观察到。此外，AGRE 组中血浆谷氨酰胺水平与 ASD 中限制和重复行为（RRB）的严重程度呈负相关，但在 NLGN1 基因型与 RRB 严重程度之间未观察到直接关联。
我们的研究结果表明，血浆谷氨酰胺水平可能作为内表型，从而在与 NLGN1 相关的遗传风险与 ASD 中 RRB 的严重程度之间建立联系。该鉴定出的关联可能有助于开发新的治疗靶点，有助于为临床试验选择特定队列，并为未来 ASD 治疗策略提供目标症状的见解。
这项工作得到了美国国立卫生研究院（R01MH107205、U01TR002623、R24OD024622、OT2OD032720 和 R01NS129188）和波士顿儿童医院 PrecisionLink 健康发现生物库的支持。
