Post-stroke depression (PSD) is a prevalent complication of stroke events, affecting approximately one-third of stroke survivors at any given time after a stroke. Individuals with PSD have a poor prognosis, with prolonged hospital stays, impaired neurological recovery, recurrent vascular events, poor quality of life, and increased mortality, leading to serious negative consequences for individuals, families, and society (1, 2). Identifying susceptibility factors for PSD is crucial. Accumulating evidence suggests that PSD development is influenced by various factors, including biological and psychosocial factors (2). Additionally, genetic links have been established between PSD and the apolipoprotein E gene, inflammatory cytokine genes, methylenetetrahydrofolate reductase gene, and brain-derived neurotrophic factor polymorphisms (3–6).

Vitamin D (VitD) is involved in many of the physiological activities of the brain, including the coordination of neurotrophic factors, immune regulation of the nervous system and neuroprotection, among other processes (7). During VitD metabolism, sunlight acts on 7-dehydrocholesterol in the skin epidermis, producing vitamin D3. The liver primarily produces 25 (OH) D through hydroxylation by the hepatic cytochrome P450 enzyme CYP2R1. The second hydroxylation to the active form 1,25 (OH)2D in the kidney is catalyzed by the cytochrome P450 enzyme CYP27B1 (8, 9). Most of the biological effects of VitD are achieved through VDR-mediated regulation. VitD binds to VDR and acts on target genes to regulate various metabolic processes, cell adhesion, tissue differentiation, development, and angiogenesis (10–12). Several studies have confirmed the association of VitD levels with PSD development. For instance, Gu et al. found that low serum VitD levels were independently associated with PSD (13, 14), consistent with previous studies (15–17). Bahrami et al. also suggested that genetic susceptibility accounts for a considerable proportion of the heterogeneity in VitD levels (8). Hence, genetic variations in the relevant genes may alter enzymatic activity in the VitD metabolic pathway, leading to altered VitD concentrations.

To the best of our knowledge, no studies have examined the association between VitD-related gene polymorphisms and PSD. Given the crucial role that VitD plays in depression pathogenesis, we selected SNP loci that may affect VitD metabolism, especially those involving exonic and 5′-flanking regions. This study aimed to investigate the association between selected SNPs in VDR (rs11568820, rs1544410, rs2228570, rs7975232, rs731236), CYP2R1 (rs12794714, rs10741657, rs7129781), CYP24A1 (rs2296241, rs2248137, rs2248359, rs2762939, rs2296239, rs2274133), CYP27B1 (rs10877012), and PSD to identify genetic susceptibility loci for PSD and further explore its pathogenesis.

To the best of our knowledge, our study was the first to investigate the potential association between VitD-related gene polymorphisms and PSD in the Chinese population with acute ischemic stroke. We conducted multiple genetic models to analyze the selected genetic polymorphisms of CYP24A1, CYP2R1, and PSD, but did not observe any significant association. However, we observed that the CYP27B1 rs10877012 G/G genotype was associated with a reduced risk of PSD. Furthermore, we found that the rs11568820-rs1544410-rs2228570-rs7975232-rs731236 CCGAA haplotype of the VDR gene was associated with a reduced risk of PSD, indicating an 0.86-fold protective effect against PSD. These findings provide important insights into the potential genetic risk factors for PSD in stroke patients.

Numerous studies have investigated the association between five SNPs in the VDR gene and depression. For instance, Kuningas et al. demonstrated that the VDR BsmI (C/T) and TaqI (A/G) genotypes could influence cognitive function and depressive symptoms (27). Similarly, other researchers have explored the role of TaqI, ApaI, and BsmI polymorphisms of the VDR gene in different contexts. A study analyzing 748 study participants found that TaqI C/C or C/T genotype was associated with emotional response and that patients with autoimmune hepatitis carrying TaqI C/C, BsmI A/A, and ApaI A/A had worse physical, social, emotional, and psychological functioning (28). Another study of survival and health effects in people over 90 years old showed that carriers of VDR rs2228570 A/A and/or G/A had little effect on longevity but may affect a variety of pathophysiologically relevant functions, including a significantly lower prevalence of depression (29). However, some researchers have reached opposing conclusions. For example, Groot et al. investigated the association between VitD levels, selected VitD synthesis-related genes, and depressive symptoms. They found that low serum 25 (OH) D levels were associated with higher depressive symptom scores, but no association was found between selected VitD loci and depression (30). A matched case–control study conducted by Lye et al. in Kuala Lumpur and Selangor included 600 participants genotyping three adjacent SNPs (BsmI, ApaI, and TaqI) of the VDR gene. They found no statistical association between the nine genotypes of BsmI, ApaI, and TaqI and the risk of developing major depression, but the BsmI-ApaI-TaqI TAC (BAt) haplotype of the VDR gene increased susceptibility to major depression (31). Our study also investigated the association between VDR gene polymorphisms and PSD in a Chinese acute ischemic stroke population. Interestingly, we found that the CCGAA haplotype of the VDR gene was associated with a reduced risk of PSD. It is important to note that the study by Lye et al. was conducted in a major depression population, which is notably inconsistent with a stroke population.

To the best of our knowledge, there have been no studies investigating the relationship between the CYP2R1 gene and depression in the context of acute ischaemic stroke. However, a meta-analysis conducted in 2018 reported that the rs10741657 A/A genotype of the CYP2R1 gene influences 25 (OH) D levels and is associated with VitD deficiency (32). Previous genome-wide association studies have identified a robust association between CYP2R1 A/G and CYP24A1 T/C genotypes and VitD levels (33). Adalı et al. found that genotype frequencies and polymorphic allele frequencies of CYP24A1 rs927650 and CYP2R1 rs10741657 were not associated with ischaemic stroke risk in the Turkish population (34). It is important to note that our study did not find an association between the genotype and allele frequencies of CYP2R1 rs7129781, rs10741657, and rs12794714 and PSD in the Chinese acute ischaemic stroke population. However, it should be acknowledged that the association between CYP2R1 and PSD in patients with onset beyond 2 weeks still requires further clarification, as our study did not conduct longer follow-up assessments.

CYP24A1 is an important regulator of blood circulation and intracellular VitD levels, playing a critical role in activating and regulating various cellular pathways (10). The CYP24A1 rs1570669 A/G genotype reduced susceptibility to ischemic stroke in both female and male patients, while the rs2296241 A/G genotype reduced risk only in male patients. Conversely, the rs6068816 T/C and rs2762934 A/G genotypes were associated with an increased risk of ischemic stroke (35). Rats exhibiting depression-like symptoms demonstrated increased expression of CYP27B1, CYP24A1 and VDR in the hippocampus and elevated levels of 1,25 (OH)2D (36). However, another animal study showed no change in CYP27B1 and CYP24A1 expression in the kidneys of depressed rats (37). In a post-mortem study of suicide conducted by Postolache et al. increased expression of the VDR gene and regular expression of the CYP27B1 or CYP24A1 genes were observed in the brains of depressed patients (38). Unfortunately, our study did not reveal any statistical association between the selected CYP24A1 locus and the development of PSD, suggesting that this relationship may need to be explored in future studies with larger sample populations.

CYP27B1, which is essential for the VitD metabolic pathway, serves as the 1-α-hydroxylase in humans (39). Although no studies have investigated the relationship between CYP27B1 and PSD, animal studies have revealed that increased CYP27B1 expression is associated with depression (36). Moreover, previous research has demonstrated that inactivation or deletion of CYP27B1 due to mutations causes VitD-dependent rickets type 1 (10, 40). Fam et al. reported that the CYP24A1 rs2762939 G/G genotype was significantly associated with stroke-like vascular acute events, also known as acute coronary syndrome, while the genotypes of CYP24A1 rs4809960 and CYP27B1 rs703842 were not associated with the incidence of acute coronary syndrome (41). In our study, we found a protective effect of the CYP27B1 rs10877012 G/G genotype compared to the rs10877012 T/T-G/T genotypes in relation to PSD (OR: 0.41, 95% CI: 0.18–0.92, p = 0.030), indicating that genes involved in the VitD metabolic pathway may play a role in the development of PSD. Although the functional annotation analysis suggests a potential association of the CYP27B1 rs10877012 variant with encoding a transcript intron, the underlying mechanisms of its impact on PSD remain unknown. Further investigations using animal models will be necessary to explore the current findings.

In addition, an authoritative meta-analysis showed that the prevalence of early-onset PSD seems to be higher than the one-third reported in most studies, at around 48% (42), which is consistent with our study findings. We used HAMD-17 to identify PSD, while some previous PSD studies have used DSM-5, the nine-item Patient Health Questionnaire, the Center of Epidemiological Studies-Depression Scale, and the Hospital Anxiety and Depression Scale (43–45). Although these tools have been proven to be useful in stroke and are suitable for interviewers to manage depression symptoms discovery or screening tools in busy clinical environments, the heterogeneity between different scales may have led to inconsistent prevalence rates of post-stroke depression.

Our study provides important insights into the genetic pathogenesis of PSD by exploring the association between VitD-related genes and PSD. However, there are several limitations that need to be acknowledged. Firstly, the current study is limited by a small sample size, which is partly due to the heavy clinical workload during the COVID-19 pandemic and China’s zero-clearance policy, which restricted the enrollment of additional eligible patients. Our research, as a preliminary discovery, needs to be validated in a larger sample size to confirm the reliability of our findings. Secondly, our study was conducted primarily in the Chinese Han population, and ethnic differences in PSD may limit the generalizability of our results. Research on other populations in the future remains necessary. Finally, the occurrence of PSD is influenced by multiple factors, including environmental factors, which were not comprehensively assessed in our study. Therefore, further investigations are needed to examine the role of environmental factors and their interactions with genetic factors in the development of PSD.

In conclusion, our study suggests that the CYP27B1 rs10877012 G/G genotype may act as a genetic protective factor for PSD, while no association was found between the selected CYP24A1 and CYP2R1 gene polymorphisms and PSD. Moreover, the VDR rs11568820-rs1544410-rs2228570-rs7975232-rs731236 CCGAA haplotype was found to be associated with a reduced risk of PSD. These findings indicate that the polymorphisms of VitD metabolic pathway genes VDR and CYP27B1 may be involved in the development of PSD in the Chinese ischemic stroke population. Further research is needed to verify these findings.

The original contributions presented in the study are included in the article/Supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethical Investigation and Review Committee of Xiangya Hospital, Central South University. The patients/participants provided their written informed consent to participate in this study.

FT and XH conceived, designed the overall research, and provided important comments on the revision of the article. DS wrote the first manuscript. All authors were involved in the collection, monitoring of the data, and revision of the article, and reviewed and agreed to the submitted version.

This work was supported by the China International Medical Foundation (Z-2016-20-2101-03), the National Key Research and Development Program of China (No. 2017YFC1310003), and the Natural Science Foundation of Hunan Province, China (2021JJ41018).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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