Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, Institute of Precision Medicine, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Nutrients. 2023 Dec 26;16(1):79. doi: 10.3390/nu16010079.
Observational studies have implied a potential correlation between allergic diseases and major depressive disorder (MDD). However, the relationship is still inconclusive as it is likely to be interfered with by substantial confounding factors and potential reverse causality. The present study aimed to investigate causal correlation of the two diseases by a Mendelian randomization (MR) study and further elucidate the underlying molecular mechanisms.
With the biggest summary datasets of a genome-wide association study (GWAS) in the East Asian population, we conducted a two-sample, bidirectional MR study to assess the causal correlation between shrimp allergy (SA) and MDD. Subsequently, we identified the pleiotropic genes' susceptibility to the two diseases at whole-genome and tissue-specific levels, respectively. Enriched GO sets and KEGG pathways were also discovered to elucidate the potential underlying mechanisms.
With the most suitable MR method, SA was identified as a causal risk factor for MDD based on three different groups of independent genetic instruments, respectively ( < 2.81 × 10). In contrast, we did not observe a significant causal effect of MDD on SA. The GWAS-pairwise program successfully identified seven pleiotropic genetic variants (PPA3 > 0.8), indicating that the two diseases indeed have a shared genetic basis. At a whole-genome level, the MAGMA program identified 44 pleiotropic genes, which were enriched in allergy-related pathways, such as antigen processing and presentation pathway ( = 1.46 × 10). In brain-specific tissue, the S-MultiXcan program found 17 pleiotropic genes that were significantly enriched in immune-related pathways and GO sets, including asthma-related pathway, T-cell activation-related, and major histocompatibility complex protein-related GO sets. Regarding whole-blood tissue, the program identified six pleiotropic genes that are significantly enriched in tolerance induction-related GO sets.
The present study for the first time indicated a significant causal effect of SA on the occurrence of MDD, but the reverse was not true. Enrichment analyses of pleiotropic genes at whole-genome and tissue-specific levels implied the involvement of allergy and immune-related pathways in the shared genetic mechanism of the two diseases. Elucidating the causal effect and the acting direction may be beneficial in reducing the incidence rate of MDD for the massive group of SA patients in the East Asian region.
观察性研究表明，过敏性疾病与重度抑郁症（MDD）之间可能存在潜在的相关性。然而，由于可能受到大量混杂因素和潜在反向因果关系的干扰，这种关系仍然不确定。本研究旨在通过孟德尔随机化（MR）研究来调查这两种疾病的因果关系，并进一步阐明潜在的分子机制。
利用东亚人群最大的全基因组关联研究（GWAS）汇总数据集，我们进行了两样本、双向 MR 研究，以评估虾过敏（SA）和 MDD 之间的因果关系。随后，我们分别在全基因组和组织特异性水平上确定了易感两种疾病的多效性基因。还发现了富集的 GO 集和 KEGG 途径，以阐明潜在的机制。
使用最合适的 MR 方法，根据三组独立的遗传工具，分别发现 SA 是 MDD 的一个因果危险因素（<2.81×10）。相比之下，我们没有观察到 MDD 对 SA 的显著因果影响。GWAS-pairwise 程序成功识别了七个多效性遗传变异（PPA3>0.8），表明这两种疾病确实具有共同的遗传基础。在全基因组水平上，MAGMA 程序识别出 44 个多效性基因，这些基因富集在过敏相关途径中，如抗原加工和呈递途径（=1.46×10）。在大脑特异性组织中，S-MultiXcan 程序发现了 17 个多效性基因，这些基因在免疫相关途径和 GO 集中显著富集，包括哮喘相关途径、T 细胞激活相关和主要组织相容性复合物蛋白相关 GO 集。关于全血组织，该程序确定了六个多效性基因，这些基因在诱导耐受相关 GO 集中显著富集。
本研究首次表明 SA 对 MDD 发生有显著的因果影响，但反之则不然。全基因组和组织特异性水平上多效性基因的富集分析表明，过敏和免疫相关途径参与了这两种疾病的共同遗传机制。阐明因果关系和作用方向可能有助于降低东亚地区大量 SA 患者的 MDD 发病率。
