Shared genetic risk factors for depression and stroke
Introduction
Both cerebrovascular disease (CVD) and depression are common and represent a large burden on the health of the elderly. There is a growing body of evidence suggesting a bi-directional relationship between stroke and depression: 1) depression can cause stroke and transient ischemic attack; and 2) stroke is associated with the increased risk for depression (Gothe et al., 2012). Stroke often causes physical and cognitive dysfunction in the elderly, which might contribute to the development of depressive mood. Depressive symptoms are very common in stroke survivors, whereby the prevalence of post-stroke depression (PSD) is estimated to be 33% in the acute phase of stroke (Mitchell et al., 2017). Depression is associated with prominent risk factors for stroke, such as diabetes, hypertension, hypercholesterolemia and obesity. Depression is also associated with poor prognosis after stroke. A large meta-analysis demonstrated that depression can increase the morbidity and mortality of stroke significantly (Pan et al., 2011).
The mechanisms underlying the association between depression and stroke is poorly investigated. Both stroke and depression are multi-factorial diseases, with both genetic and environmental factors likely to participate in their pathogenesis. The heritability of major depressive disorder (MDD) is estimated to be in the range of 31 to 42% (Kendler et al., 2006). Depression pathogenesis is thought to be influenced by multiple risk factor genes, and the inheritance pattern is extremely complex, polygenic and epistatic (López-León et al., 2008). For all ischemic stroke (IS), heritability is estimated to be 37.9%, and genetic predisposition differs for different subtypes, with large-vessel atherosclerotic stroke (LAS) exhibiting the highest heritability (40.3%) (Bevan et al., 2012). The vast majority of stroke appears to be polygenic in heritability (Dichgans, 2007).
Considering the genetic involvement in the pathogenesis of both stroke and depression as well as the frequent comorbidity of them, it is reasonable to suppose that there are shared genetic risks for both stroke and depression. We found that genetic polymorphisms of many genes are associated with the susceptibility of both stroke and depression, such as methylenetetrahydrofolate reductase (MTHFR) (Bondarenko et al., 2016; Liew and Gupta, 2015), angiotensin converting enzyme (ACE) (Baghai et al., 2006a; Mostafa et al., 2016; Munshi et al., 2008), apolipoprotein E (ApoE) (Evans and Rajan, 2015; Chatzistefanidis et al., 2014a; Khan et al., 2013a), serum paraoxonase (PON1) (Lawlor et al., 2007a; Liu et al., 2011a; Li et al., 2016a), and many inflammatory cytokines including pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) (Niu et al., 2015a; Wawrzynek et al., 2014), interleukin-1β (IL-1β) (Chehaibi et al., 2015; Rezk and Mohamad, 2015) and interleukin-6 (IL-6) (Kumar et al., 2016a; Kumar et al., 2016b), and anti-inflammatory cytokines like interleukin-4 (IL-4) and interleukin-10 (IL-10) (Su et al., 2012). This review was aimed to summarize studies investigating the risk genes and their identified genetic polymorphisms for both depression and stroke and outline the potential biological processes underlying this association.
Section snippets
Data sources
A meta-analysis and systematic review were performed (Fig. 1). Genetic case-control association studies, as well as meta-analyses regarding genetic risk for stroke and depression,were searched in the database PubMed before December 2018. The searching keywords included “gene polymorphism”, “genetic variants”, “risk factor” in combination with “depression”, “depressive mood” or “stroke”. In the brief search at first, some shared candidate genes and their identified polymorphisms (MTHFR C677T,
MTHFR gene and depression
The association between the MTHFR C677T polymorphism and depression has been investigated by numerous studies. The results of these association studies are inconsistent (Bondarenko et al., 2016; Delport et al., 2014; Yuan et al., 2008), and the difference might be due to varied ethnic backgrounds and age range. Several meta-analyses accessing the relationship have supported that the MTHFR C677T polymorphism, precisely the TT genotype, is associated with the increased risk of depression (Rai,
ACE gene and stroke
Many studies confirmed the effect of ACE I/D gene polymorphism on risk of stroke and found that DD genotype and D allele carriers are more susceptible to IS (Mostafa et al., 2016; Della-Morte et al., 2013; Hong et al., 2008). However, there are also some inconsistent or contradictory results, e.g. II genotype and I allele is found significantly associated with ischemic stroke in an Indian male population (Vijayan et al., 2014). It is further complicated by the evidence that the frequency of DD
ApoE gene and stroke
According to the various studies examining the role of ApoE gene polymorphisms in stroke occurrence, ApoE might have an ethnic- and sex-related effect on the susceptibility of stroke (Hermann, 2014). The ApoE ε4 allele has been implicated many times in stroke and ε4 carriers are estimated to have 2.66-fold greater likelihood of IS than non-carriers (Zhao et al., 2017; Konialis et al., 2016; Boumendjel et al., 2013). The genotype ε3/ε3 is reported with a potential protective role against stroke
PON1 gene and stroke
The Q192R polymorphism of PON1 gene has been examined in multiple genetic association studies observing its relationship with susceptibility of IS. The R allele and the RR genotype of Q192R polymorphism have been associated with an increased risk for IS (Liu et al., 2010; Can et al., 2008; Ranade et al., 2005). However, some studies do not replicate this finding (Yang et al., 2012; Demirdogen et al., 2009). A gene-diet interaction is demonstrated by a Chinese family-based case control study
Inflammatory cytokine genes
Alterations in inflammation are involved in the development of both MDD and stroke. An increasing number of studies have focused on these candidate genes (such as CRP, IL-1, IL-6 and TNF-α) for their influence on the risk of depression and stroke, though many conflicting results exist. The precise mechanism by which inflammatory cytokines mediate the pathogenesis of both stroke and depression is poorly understood yet, but the association may be explained by several aspects: 1) increased
Serotoninergic gene
Impaired serotonin signaling is involved in the pathogenesis of MDD, while few studies have explored the association between serotoninergic genes and stroke.
The serotonergic function is mainly regulated by the serotonin transporter (5-HTT) gene and serotonin receptor (5-HTR) gene. Multiple studies have shown that the short (s) allele in the 5-HTTLPR, which results in lower levels of 5-HTT expression, is associated with a higher risk of depression when combined with stressful life events (Fisher
Neurotrophic genes
Brain-derived neurotrophic factor (BDNF) is gathering intense concern on its association with stroke and depression for the role in neuroplasticity, neuroprotection and neurogenesis.
Other genes
Some other polymorphisms are reported to influence the development of PSD, while they have been barely studied in either depression or stroke.
Catechol-O-methyltransferase (COMT) degrades over 60% dopamine (DA) in forehead cortical synapses through methylation and thus is associated with mood disorders. A G-A point mutation in exon 4 which makes the coding of 108 or 158 amino acid Val instead by Met, causes a 3–4 folds reduction in the enzyme activity. Cai (WW C, 2011) explored the association
Conclusions and outlook
In this review, the identified polymorphisms of MTHFR, ApoE, ACE and PON1 are summarized to influence risk of both depression and stroke. The existing data support the hypothesis that shared genetic mechanisms may contribute to the comorbidity of stroke and depression. For MTHFR and ApoE, their relationship with depression and stroke has been confirmed in the latest meta-analysis. But for ACE I/D and PON1 Q192R polymorphism, their association with depression is still under debate, since the
Financial support and sponsorship
This work was supported by National Key Technology R&D Program (2015BAI13B01).
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
Fuying Zhao: literature search, figure and table making, data collection and writing.
Yingying Yue and Haitang Jiang: paper correction.
Yonggui Yuan: study design and paper correction.
References (232)
- et al.
An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders
Biol Psychiatry
(1996) - et al.
An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders
Biol Psychiatry
(1996) - et al.
The angiotensin I converting enzyme insertion/deletion polymorphism influences therapeutic outcome in major depressed women, but not in men
Neurosci Lett
(2004) - et al.
Meta-analysis on the association between brain-derived neurotrophic factor polymorphism rs6265 and ischemic stroke, poststroke depression
J Stroke Cerebrovasc Dis
(2018) - et al.
Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment
Clin. Biochem.
(2009) - et al.
Lowered plasma paraoxonase (PON)1 activity is a trait marker of major depression and PON1 Q192R gene polymorphism–smoking interactions differentially predict the odds of major depression and bipolar disorder
J Affect Disorders
(2014) - et al.
Paraoxonase 1 status and interactions between Q192R functional genotypes by smoking contribute significantly to total plasma radical trapping antioxidant potential
Neurosci. Lett.
(2014) - et al.
Paraoxonase (PON1) polymorphisms in farmers attributing ill health to sheep dip
Lancet
(2002) - et al.
Meta-analysis in clinical trials revisited
Contemp Clin Trials
(2015) Genetics of ischaemic stroke
Lancet Neurol
(2007)