The association between cytomegalovirus infection and neurodegenerative diseases: a prospective cohort using UK Biobank data

Abstract

Background: Certain viral infections have been linked to the development of neurodegenerative diseases. This study aimed to investigate the association between cytomegalovirus (CMV) infection and five neurodegenerative diseases, spinal muscular atrophy (SMA) and related syndromes, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and disorders of the autonomic nervous system (DANS).

Methods: This prospective cohort included white British individuals who underwent CMV testing in the UK Biobank from January 1, 2006 to December 31, 2021. A Cox proportional hazard model was utilized to estimate the future risk of developing five neurodegenerative diseases in individuals with or without CMV infection, adjusted for batch effect, age, sex, and Townsend deprivation index in Model 1, and additionally for type 2 diabetes, cancer, osteoporosis, vitamin D, monocyte count and leukocyte count in Model 2. Bidirectional Mendelian randomization was employed to validate the potential causal relationship between CMV infection and PD.

Findings: A total of 8346 individuals, consisting of 4620 females (55.4%) and 3726 males (44.6%) who were white British at an average age of 56.74 (8.11), were included in this study. The results showed that CMV infection did not affect the risk of developing AD (model 1: HR [95% CI] = 1.01 [0.57, 1.81], P = 0.965; model 2: HR = 1.00 [0.56, 1.79], P = 0.999), SMA and related syndromes (model 1: HR = 3.57 [0.64, 19.80], P = 0.146; model 2: HR = 3.52 [0.63, 19.61], P = 0.152), MS (model 1: HR = 1.16 [0.45, 2.97], P = 0.756; model 2: HR = 1.16 [0.45, 2.97], P = 0.761) and DANS (model 1: HR = 0.65 [0.16, 2.66], P = 0.552; model 2: HR = 0.65 [0.16, 2.64], P = 0.543). Interestingly, it was found that participants who were CMV seronegative had a higher risk of developing PD compared to those who were seropositive (model 1: HR = 2.37 [1.25, 4.51], P = 0.009; model 2: HR = 2.39 [1.25, 4.54], P = 0.008) after excluding deceased individuals. This association was notably stronger in males (model 1: HR = 3.16 [1.42, 7.07], P = 0.005; model 2: HR = 3.41 [1.50, 7.71], P = 0.003), but no significant difference was observed in the female subgroup (model 1: HR = 1.28 [0.40, 4.07], P = 0.679; model 2: HR = 1.27 [0.40, 4.06], P = 0.684). However, a bidirectional Mendelian randomization analysis did not find a genetic association between CMV infection and PD.

Interpretation: The study found that males who did not have a CMV infection were at a higher risk of developing PD. The findings provided a new viewpoint on the risk factors for PD and may potentially influence public health approaches for the disease.

Funding: National Natural Science Foundation of China (81873776), Natural Science Foundation of Guangdong Province, China (2021A1515011681, 2023A1515010495).

Keywords: Bidirectional Mendelian randomization analysis; Cox proportional hazards model; Cytomegalovirus; GWAS; Parkinson’s disease.

Fig. 1

Flowchart of the study.

Fig. 2

Restricted cubic splines (RCS) assessing the nonlinear association between CMV infection and Parkinson’s disease (PD). (A) No nonlinear association between CMV pp28 and PD was shown (P for nonlinear = 0.465). (B) No nonlinear association between CMV pp52 and PD was shown (P for nonlinear = 0.474). (C) No nonlinear association between CMV pp150 and PD was shown (P for nonlinear = 0.243). Shaded areas represent 95% CIs. (D) The event rate of PD patients with different levels of CMV pp28 titers was shown. (E) The event rate of PD patients with different levels of CMV pp52 titers was shown. (F) The event rate of PD patients with different levels of CMV pp150 titers was shown. Titer levels were divided into quartiles of Q1-Q4. Abbreviation: RCS, Restricted cubic splines; CMV, cytomegalovirus; PD, Parkinson’s disease; CI, confidence interval.

Fig. 3

The HR of PD is presented based on different CMV titers (Q1–Q4) stratified by sex. Model 1 (red) was adjusted for batch, age, sex and TDI. Model 2 (blue) was adjusted for batch, age, sex, TDI, T2D, cancer, OP, vitamin D, monocyte count and white blood cell leukocyte count. (A–C) The hazard ratio (HR) of developing PD varies with different levels of pp150, pp28 and pp52 in overall population. (D–F) The HR of developing PD varies with different levels of pp150, pp28 and pp52 in females. (G–I) The HR of developing PD varies with different levels of pp150, pp28 and pp52 in males. Abbreviation: HR, hazard ratio; TDI, Townsend deprivation Index; T2D, type 2 diabetes; OP, osteoporosis.

Fig. 4

Genome-wide association study. In Manhattan plots, each point represents the location of a SNP on the chromosome (x-axis) and −log10 (P-value) for the strength of its association (y-axis). The red line indicating the threshold for −log10 (5E⁻⁷). The SNP above the red line is with strongly associated with the CMV. Abbreviation: SNP, single nucleotide polymorphism.

Fig. 5

The genome-wide MAGMA analysis for SNPs. The genome-wide MAGMA analysis revealed the tissue-specifical distribution of SNPs, providing a ranking of tissues that are significantly associated with CMV. Abbreviation: MAGMA, multimarker analysis of genomic annotation.

Fig. 6

No causality between the CMV infection and PD was established in BMR analysis. (A) Scatter plot shows no causal effect of CMV on Parkinson’s disease. Each point represents a SNP, with the line at each point showing its 95% confidence interval. The horizontal axis represents the effect of the SNP on the exposure factor (CMV), while the vertical axis represents the effect on the outcome factor (PD). The colored lines indicate the effect of exposure on outcome, with the red representing the IVW algorithm, the green representing the MR-Egger algorithm and the blue representing weighted median algorithm. (B) The funnel plot shows the heterogeneity of the SNPs, with the red representing the IVW algorithm, the green representing the MR-Egger algorithm and the blue representing weighted median algorithm. The points on both sides of the line are fairly symmetrical, with no significant outliers, suggesting low heterogeneity of the SNPs. (C) Scatter plot of the causal effect of Parkinson’s disease on CMV. (D) Funnel plot of the causal effect of Parkinson’s disease on CMV. Abbreviation: BMR, bidirectional Mendelian randomization.