背景:观察性研究表明,过敏性疾病与重度抑郁症(MDD)之间存在潜在的相关性。然而,这种关系仍然没有定论,因为它很可能受到实质性混杂因素和潜在的反向因果关系的干扰.本研究旨在通过孟德尔随机化(MR)研究来研究两种疾病的因果关系,并进一步阐明潜在的分子机制。
方法:根据东亚人群全基因组关联研究(GWAS)的最大摘要数据集,我们做了两个样本,双向MR研究,以评估虾过敏(SA)和MDD之间的因果关系。随后,我们在全基因组和组织特异性水平上鉴定了对这两种疾病的多效性基因易感性,分别。还发现了富集的GO集和KEGG途径以阐明潜在的潜在机制。
结果:使用最合适的MR方法,根据三组不同的独立遗传工具,SA被确定为MDD的因果风险因素,分别为(p<2.81×10-2)。相比之下,我们没有观察到MDD对SA的显著因果效应.GWAS-pairwise程序成功鉴定出7种多效遗传变异(PPA3>0.8),这表明这两种疾病确实有共同的遗传基础。在全基因组水平上,MAGMA程序确定了44个多效性基因,它们富含与过敏相关的途径,如抗原加工和提呈途径(p=1.46×10-2)。在大脑特定组织中,S-MultiXcan程序发现了17种多效基因,这些基因在免疫相关途径和GO集合中显著富集,包括哮喘相关途径,T细胞活化相关,和主要组织相容性复杂蛋白质相关的GO集。关于全血组织,该程序鉴定了6个多效性基因,这些基因在耐受诱导相关的GO集合中显著富集。
结论:本研究首次表明SA对MDD的发生具有显著的因果关系,但事实并非如此。在全基因组和组织特异性水平上对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。阐明因果效应和作用方向可能有助于降低东亚地区大量SA患者的MDD发生率。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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 (p < 2.81 × 10-2). 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 (p = 1.46 × 10-2). 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.
CONCLUSIONS: 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.