Phenome-wide investigation of bidirectional causal relationships between major depressive disorder and common human diseases

Abstract

The high comorbidity of major depressive disorder (MDD) with other diseases has been well-documented. However, the pairwise causal connections for MDD comorbid networks are poorly characterized. We performed Phenome-wide Mendelian randomization (MR) analyses to explore bidirectional causal associations between MDD (N = 807,553) and 877 common diseases from FinnGen datasets (N = 377,277). The inverse variance weighting method was the primary technique, and other methods (weighted median and MR-Egger) were used for sensitivity analyses. Our MR analyses showed that the genetic liability to MDD is causally associated with the risks of 324 disease phenotypes (average b: 0.339), including 46 psychiatric and behavioral disorders (average b: 0.618), 18 neurological diseases (average b: 0.348), 44 respiratory diseases (average b: 0.345), 40 digestive diseases (average b: 0.281), 18 circulatory diseases (average b: 0.237), 37 genitourinary diseases (average b: 0.271), 66 musculoskeletal and connective diseases (average b: 0.326), 22 endocrine diseases (average b: 0.302), and others. In a reverse analysis, a total of 51 genetic components predisposing to various diseases were causally associated with MDD risk (average b: 0.086), including 5 infectious diseases (average b: 0.056), 11 neurological diseases (average b: 0.106), 14 oncological diseases (average b: 0.108), and 5 psychiatric and behavioral disorders (average b: 0.114). Bidirectional causal associations were identified between MDD and 15 diseases. For most MR analyses, little evidence of heterogeneity and pleiotropy was detected. Our findings confirmed the extensive and significant causal role of genetic predisposition to MDD in contributing to human disease phenotypes, which were more pronounced than those seen in the reverse analysis of the causal influences of other diseases on MDD.

Fig. 1. Study design overview.

A total of 877 phenotypes were included. With adjusted p-values at the significance level (FDR < 0.05), genetically predicted depression was associated with a total of 324 disease phenotypes. In turn, a total of 51 genetically predicted disease phenotypes were associated with depression. Among these, bidirectional causal associations with depression were detected for 15 disease phenotypes. MR, Mendelian randomization; FDR, False discovery rate.

Fig. 2. The Beta value plot of the 2-sample MR analysis.

a Volcano plot of MDD on other diseases in the FinnGEN database. b Volcano plot of other diseases in the Finnish database on MDD. The Beta value is used as the X-axis and -lg(FDR-Value) is used as the Y-axis. The FDR-Values were cut off at the 1.00E-5 level. The red dotted line indicates the level of statistical significance (FDR <0.05). c Violin plot of the MR and reverse MR analysis. The Beta value is used as the Y-axis and groups are used as the X-axis. Group 1: the Beta value plot of MDD on other diseases in the FinnGEN database. Group 2: the Beta value plot of other diseases in the Finnish database on MDD. FDR false discovery rate.

Fig. 3. The OR value plot of the effects of other disorders and MDD.

a The OR value plot of the effects of other disorders on MDD in the two-sample MR analysis. The causal impact of other disorders on depression is characterized by a wide range of disorders with strong and significant differences in their contributions, with the more prominent ones being emotionally unstable personality disorder (OR = 3.02), personality disorders (more control exclusions) (OR = 2.66), mixed and other personality disorders (OR = 2.46), any mental disorder, or suicide (or attempt), or psychic disorders complicating pregnancy, partum or puerperium or nerve system disorders (OR = 2.44), fibromyalgia (OR = 2.33), panic disorder (OR = 2.30), hyperkinetic disorders (OR = 2.22), other and unspecified mood [affective] disorders (OR = 2.17), other anxiety disorders (OR = 2.16). KRA_PSY_ANYMENTAL_SUICID_PREG_NERV_EXMORE: any mental disorder, suicide (or attempt), or psychic disorders complicating pregnancy, partum or puerperium or nerve system disorders (more control exclusions); F5_BEHEMOCHILD: behavioural and emotional disorders with onset usually occurring in childhood and adolescence; F5_OTHERSUB: mental and behavioral disorders due to multiple drug use and use of multiple drugs and use of other psychoactive substances; VWXY20_INTENTI_SELF_P_EXPOS_OTHER_UNSPE_CHEMIC_NOXIO_SUBST: intentional self-poisoning by and exposure to other and unspecified chemicals and noxious substances. The β-values were cut off at the 0.50 level. b The OR value plot of the effects of MDD on other disorders in the 2-sample MR analysis. The causal impact of depression on other disorders is characterized by a relatively limited variety of disorders with restricted and non-significant differences in contribution, with the more prominent ones being haemangioma and lymphangioma, any site (OR = 1.41), benign neoplasm of the eye and adnexa (OR = 1.31), and benign lipomatous neoplasm of other sites/unspecified (OR = 1.30).

Fig. 4. The depression and its comorbid conditions: shared pathophysiology.

The numerous risk factors involved such as genetics, childhood trauma, individual traits, stress, socially undesirable environments, and unhealthy behavioral patterns may contribute to co-morbid depression in those with medical disorders. The potential link between depression and medical disorders is established through one or more pathway mechanisms, encompassing behavioral, biological, and psychological factors. The figure was drawn by Figdraw.