(2023) 21:203
Ohi ﻿BMC Medicine
https://doi.org/10.1186/s12916-023-02905-8

BMC Medicine

COMMENTARYOpen Access

Shared genetic correlation and causal
association between major depressive disorderand breast cancer
Kazutaka Ohi1,2*   

Keywords Major depressive disorder, Breast cancer, Genetic correlation, Causal association, Inflammation

Background
Major depressive disorder (MDD) and breast cancer (BC)are two distinct health conditions that can be linked inseveral ways. It is well established that cancer patients
have a higher risk of developing MDD than the general
population [1]. A diagnosis of BC can be a life-changing
event, and treatments, such as surgery, chemotherapy,and radiation therapy, can be physically and emotionallystressful. This may lead to symptoms of anger, fear, anxiety, and depression with regard to the disease and treatment process. Furthermore, some of the side effects ofBC treatment, such as pain, fatigue, and changes in hormone levels, can contribute to the development of MDD.
Thus, BC patients are more likely to experience depressive symptoms after diagnosis and treatment than individuals without BC [2]. Moreover, several studies havefound that individuals with MDD have a higher risk ofdeveloping BC than those without MDD [3–5], though
this population-based evidence remains inconsistentamong studies. Including the recent large-scale longitudinal follow-up study from the UK Biobank by Wu et al.
(2023), individuals with MDD reportedly have a 1.1- to2.5-fold increased risk of developing BC compared to*Correspondence:
Kazutaka Ohi
k_ohi@gifu-u.ac.jp
1
Department of Psychiatry, Gifu University Graduate School of Medicine,
1‑1 Yanagido, Gifu 501‑1194, Japan2
Department of General Internal Medicine, Kanazawa Medical University,Ishikawa, Japan

those without MDD. Although there is evidence to suggest that BC may increase the risk of developing MDD
and vice versa, further research is required to fully understand the relationship. Recently, Wu et al. (2023) havereported the phenotypic as well as genetic relationships
between MDD and BC [5].

Involvement of genetic factors in the pathogenesisof MDD and BC
Several studies have suggested that the relationship may
be due to the impacts of stress and chronic inflammationon the immune system, which might increase the risk ofboth MDD and BC. Psychosocial stressors in cancer aswell as depression itself promote inflammation and oxidative/nitrosative stress, decreased immunosurveillance,and dysfunctional activation of the autonomic nervous
system and the hypothalamic‒pituitary‒adrenal (HPA)
axis.
Genetic factors play a role in the pathogenesis of MDDand BC, with heritability estimates of 37% [6] and 31%[7], respectively. To date, large-scale genome-wide association studies (GWASs) of MDD [8] and BC [9] haveidentified over 100 and 150 genome-wide significant locirelated to these conditions, respectively. Furthermore,genetic correlations between risk of MDD and female
reproductive phenotypes such as age at menarche andmenopause (rg≈-0.12), which are well-established risk
factors for BC, have been demonstrated [8]. Wu et al.
(2023) indicated that common genetic factors play arole in the pathogenesis of both MDD and BC (rg = 0.08)
regardless of subtype based on the status of estrogen© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, whichpermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
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Ohi B﻿ MC Medicine(2023) 21:203

receptor (ER) (ER + , rg = 0.06; ER–, rg = 0.08) [5]. In addition, Wu et al. (2023) identified shared specific local
genomic regions, such as at 6p22.1, shared specific loci atthe individual variant level, such as rs2403907 at 21q21.1,
shared genes, such as FLOT1 and HLA-S at 6p21.33,
enriched in specific tissues including brain, blood, uterus,colon, artery and heart, and shared genetic functions,such as immune, inflammatory, and stress responses [5],which may be involved in the development of both MDD
and BC. These findings support that MDD and BC may
be linked by shared biology.

Causal association between MDD and BC
There is evidence for an association between MDD andBC based on observational studies and genetic studies,though the direct causal relationship between the two
conditions is not yet fully understood. Mendelian randomization (MR) analysis is a method that uses genetic
variants associated with exposure as instrumental variables to establish causal relationships between exposures and outcomes. MR analysis depends on the natural
randomized assortment of genetic variants, making it
an analog for randomized controlled trials, and it canbe used to infer causality in large-scale GWAS datasets.
Using MR analysis, bidirectional causal associations
between MDD and BC were investigated in two independent studies [5, 10], including the recent study by Wu
et al. (2023). Both studies detected the causal effect of
MDD on BC (OR = 1.09–1.12), but the causal effect of BC
on MDD was not detected (OR = 1.00–1.01) [5, 10]. MDD
was associated with an increased risk of BC. In subgroup
analysis divided by ER status, the effect of depression on
ER– BC (OR = 1.10–1.12) was slightly stronger than thatof depression on ER + BC (OR = 1.07–1.08). Similarly,
there was no evidence of reverse causality associatedwith ER status.
Conclusions
In light of the new findings of Wu et al. (2023) [5], thisarticle discusses the association between MDD and BC,
the extent to which these conditions coexist in observation studies, and the extent to which genetic factors playa role in the pathogenesis of both conditions. BC and its
treatment can cause physical and emotional stress, leading to MDD development. Conversely, MDD is a risk factor for BC development. There is evidence to suggest that
MDD and BC have shared genetic influences, with largescale GWASs identifying multiple significant loci related
to MDD and BC and these genetic correlations. Additionally, the causal relationship between MDD and BC isdiscussed herein. The potential causal effect of MDD on
BC is suggested, but reverse causality has not been identified. Overall, environmental factors, including physicalPage 2 of 3and emotional stress associated with the diagnosis andtreatment of BC, may contribute to the development ofMDD in BC patients, and there may be a biological link
between MDD and BC, with chronic inflammation andother biological changes associated with MDD potentially increasing risk of BC. These findings highlight theimportance of physicians addressing the physical andemotional needs of patients with these conditions andthe importance of mental health in the prevention andtreatment of BC.
Acknowledgements
Not applicable.
Authors’ contributions
The author contributed to the writing of the manuscript and approved thefinal manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The author declares no competing interests.
Received: 1 May 2023 Accepted: 22 May 2023

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