Activated immune–inflammatory pathways are associated with long-standing depressive symptoms: Evidence from gene-set enrichment analyses in the Young Finns Study
Section snippets
Participants and design
The participants were from the Cardiovascular Risk in Young Finns Study (YFS) which is a population-based, prospective multi-center cohort study being conducted in five university hospital cities in Finland. It was initiated in 1980 (N at baseline = 3596) (Raitakari et al., 2008). Of the complete data, 2050 individuals took part in YFS follow-up examinations in 2011–2012. 2049 of them gave blood samples to RNA isolation. 16 tubes were either empty or did not contain enough blood for RNA
Results
Sample characteristics are shown in Table 1. Participants with long-standing depressive symptoms (n = 191) had a higher body mass index (BMI), exercised less and had a higher triglycerides level than those without depressive symptoms. CRP was also higher in the group of long-standing depressive symptoms. The association between gene set pathways and long-standing depressive symptoms are shown in Table 2. The strongest association (NES 1.87, nominal p value < 0.002, FDR q-val < 0.09) was found
Discussion
The current findings showed that long-standing depressive symptoms measured three times over 11 years were associated with differences in regulatory pathways expressed in peripheral blood. In this study, we were interested in pathways related to inflammatory processes and we included only those pathways that were significantly associated with repeated measure of high depressive symptoms These pathways included IL-1, toll-like pathway, the NEF protein pathway, the nuclear factor kB (NF-kB)
Contributors' statement page
ME and TL designed the study, ME drafted the initial manuscript, honed the manuscript with the co-authors and approved the final manuscript as submitted. TL was responsible for the biomedical analyses, he also reviewed and revised the manuscript, and approved the final manuscript as submitted. TT, IS, NM and ER carried out the biomedical analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. MJ., LPR, TI, MW, CH, TH, MKi, MKä, LKJ, and OTR reviewed and
Role of funding source
Any of the funders had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the article for publication.
Conflicts of interest
All authors declare no conflict of interest.
Acknowledgments
The Cardiovascular Risk in Young Finns Study has been financially supported by the Academy of Finland (grants 126925, 121584, 124282, 129378 [Salve], 117787 [Gendi], 41071 [Skidi], and 134309 [eye]); the Social Insurance Institution of Finland; the Kuopio, Tampere, and Turku University Hospital Medical Funds (grant 9N035 and X51001 for T.L.); the Juho Vainio Foundation (L.P.R.); the Paavo Nurmi Foundation; the Finnish Foundation of Cardiovascular Research (T.L., O.R.); the Finnish Cultural
References (40)
- et al.
Gene and expression analyses reveal enhanced expression of pericentrin 2 (PCNT2) in bipolar disorder
Biol. Psychiatry
(2008) Altered intracellular signaling cascades in peripheral blood mononuclear cells from BD patients
J. Psychiatr. Res.
(2013)- et al.
Finding the intracellular signaling pathways affected by mood disorder treatments
Neuron
(2003) - et al.
Altered gene expression of histone deacetylases in mood disorder patients
J. Psychiatr. Res.
(2010) - et al.
Association between toll-like receptors expression and major depressive disorder
Psychiatry Res.
(2014) - et al.
The prevalence, clinical relevance, and public health significance of subthreshold depressions
Psychiatr. Clin. North Am.
(2002) Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2011)- et al.
Depressive symptoms and personal project appraisals: a cross-lagged longitudinal study
Personal. Individ. Differ.
(1996) - et al.
Physical activity in childhood and adolescence as predictor of physical activity in young adulthood
Am. J. Prev. Med.
(1997) - et al.
Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010
Lancet
(2013)
Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010
Lancet
Associations of depressive symptoms, trait hostility, and gender with C-reactive protein and interleukin-6 response after emotion recall
Psychosom. Med.
Interferons and indoleamine 2,3-dioxygenase: role in antimicrobial and antitumor effects
Experientia
From inflammation to sickness and depression: when the immune system subjugates the brain
Nat. Rev. Neurosci.
Depressive symptoms and carotid artery intima-media thickness in young adults: the cardiovascular risk in Young Finns Study
Psychosom. Med.
Depressive symptoms and C-reactive protein: the cardiovascular risk in Young Finns study
Psychol. Med.
Depressive symptoms and C-reactive protein: the cardiovascular risk in Young Finns Study
Psychol. Med.
Depression and C-reactive protein: population-based health 2000 study
Psychosom. Med.
Indoleamine 2,3-dioxygenase (IDO) activation and depressive symptoms; results from the Young Finns study
Psychosom. Med.
Depression and C-reactive protein in US adults: data from the third national health and nutrition examination survey
Archives Intern. Med.
Cited by (18)
Brain-immune interactions in neuropsychiatric disorders: Lessons from transcriptome studies for molecular targeting
2021, Biochemical PharmacologyCitation Excerpt :For example, the activation of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome leads to a release of active forms of inflammatory cytokines IL-1β and pro-IL-18. Master regulator of inflammatory pathways, nuclear factor-κB (NF-κB), nucleotide-binding oligomerization domain, and leucine-rich repeat proteins, have been implicated in the pathophysiology of depression, SCZ, BD, and ASD [39–41]. The central effects of cytokines also rely on the activation of the NF-κB pathway, increasing c-Fos activity in multiple brain regions resulting in depressive behaviors [42].
Immune dysregulation in depression: Evidence from genome-wide association
2020, Brain, Behavior, and Immunity - HealthCitation Excerpt :Having reviewed evidence supporting a role of immune dysregulation in depression, we synthesize immune-related genes identified in the most recent GWAS meta-analysis by Howard et al. (2019) with evidence of their known biological function from existing literature. Although Howard et al. (2019) found no significant evidence for enrichment of immune-related gene-sets, other gene-set and expression studies show support for cytokine and immune-related pathway enrichment in depressed patients (Elovainio et al., 2015; Jansen et al., 2016; Leday et al., 2018; Wray et al., 2018). Thus, more research will be necessary to firmly establish gene-set enrichment, but current experimental, epidemiological, and genetic evidence linking inflammation with depression warrants a systematic evaluation of the functions of immune-related genes identified by Howard et al. (2019) as candidates for deeper depression-focused study.
The Bidirectional Relationship of Depression and Inflammation: Double Trouble
2020, NeuronCitation Excerpt :Thus, the gene expression of the ApoE receptor ApoER2 decreases in lymphocytes (Suzuki et al., 2010), whereas the gene expression of triggering receptor expressed on myeloid cells 1 (trem-1), DNAX-activation protein of 12 kDa (Dap12), and purine-rich Box-1 (pu.1) increases in monocytes of depressed patients (Weigelt et al., 2011). Furthermore, various immune-inflammatory processes, such as the nuclear factor κB (NF-κB) pathway, which is important for cytokine production as discussed later in the review, IL-1β, IL-6, and TNF signaling pathways, toll-like receptor pathway, NK cell activation pathway, IFN-α/β signaling pathway, oxidative stress pathways are affected in MDD patients’ PBMCs (Beech et al., 2010; Elovainio et al., 2015; Gałecki et al., 2012; Jansen et al., 2016; Leday et al., 2018; Mostafavi et al., 2014; Yi et al., 2012), reinforcing the idea that immune pathways contribute to MDD. Cytokines are required for the differentiation of T helper (Th) subsets, suggesting that the chronic production of cytokines found in MDD patients might influence Th cell fate.
The NCAM1 gene set is linked to depressive symptoms and their brain structural correlates in healthy individuals
2017, Journal of Psychiatric ResearchCitation Excerpt :Notably, the NETRIN1 signaling pathway was recently associated with MDD using a similar approach (Zeng et al., 2017). Furthermore, the Synaptic transmission pathway was associated with MDD and several immune-inflammatory pathways with depressive symptoms, respectively, using genome-wide expression data (Elovainio et al., 2015; Hori et al., 2016). Therefore, it was hypothesized that depression scores are related to particular gene sets in the current study.
n-3 polyunsaturated fatty acids improve depression-like behavior by inhibiting hippocampal neuroinflammation in mice via reducing TLR4 expression
2022, Immunity, Inflammation and DiseaseMulti-Omics Integration in a Twin Cohort and Predictive Modeling of Blood Pressure Values
2022, OMICS A Journal of Integrative Biology