Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
PLoS One. 2023 Nov 15;18(11):e0294045. doi: 10.1371/journal.pone.0294045. eCollection 2023.
The relaxin-3/RXFP3 system has been implicated in the modulation of depressive- and anxiety-like behaviour in the animal literature; however, there is a lack of human studies investigating this signalling system. We seek to bridge this gap by leveraging the large UK Biobank study to retrospectively assess genetic risk variants linked with this neuropeptidergic system. Specifically, we conducted a candidate gene study in the UK Biobank to test for potential associations between a set of functional, candidate single nucleotide polymorphisms (SNPs) pertinent to relaxin-3 signalling, determined using in silico tools, and several outcomes, including depression, atypical depression, anxiety and metabolic syndrome. For each outcome, we used several rigorously defined phenotypes, culminating in subsample sizes ranging from 85,881 to 386,769 participants. Across all outcomes, there were no associations between any candidate SNP and any outcome phenotype, following corrections for multiple testing burden. Regression models comprising several SNPs per relevant candidate gene as exploratory variables further exhibited no prediction of outcome. Our findings corroborate conclusions from previous literature about the limitations of candidate gene approaches, even when based on firm biological hypotheses, in the domain of genetic research for neuropsychiatric disorders.
松弛素-3/RXFP3 系统已被牵涉到动物文献中抑郁和焦虑样行为的调节中；然而，目前缺乏研究该信号系统的人类研究。我们试图通过利用大型英国生物库研究来弥补这一空白，回顾性评估与这种神经肽系统相关的遗传风险变异体。具体来说，我们在英国生物库中进行了一项候选基因研究，以测试一组使用计算机工具确定的与松弛素-3 信号传导相关的功能候选单核苷酸多态性 (SNP) 与几种结果之间的潜在关联，包括抑郁、非典型抑郁、焦虑和代谢综合征。对于每个结果，我们使用了几个严格定义的表型，最终的样本量范围从 85881 到 386769 名参与者不等。在进行了多次测试负担的校正后，所有结果中，候选 SNP 与任何结果表型之间均无关联。包含每个相关候选基因的多个 SNP 的回归模型作为探索性变量，也没有显示对结果的预测。我们的研究结果与以前文献中的结论相吻合，即即使基于坚实的生物学假设，候选基因方法在神经精神疾病的遗传研究领域也存在局限性。
