
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

MD-D-24-01328
00031
10.1097/MD.0000000000039706
3
6500
Research Article
Observational Study
Causal relationship between neuroticism and bone mineral density: A univariable and multivariable Mendelian randomization study
Chen Shangtong MM cf609226271@126.com
a
Zhong Jing DR zhongjing1212@163.com
b
https://orcid.org/0000-0003-3860-1568
Chen Yueping DR a*
Zhang Xiaoyun DR Zhangxiaoyun520@126.com
a
Huang Chuanhong MM kiloon@126.com
a
Chen Feng DR cf609226271@126.com
a
a Department of Orthopedics and Hand Surgery, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
b Physiological Department, Guangxi University of Chinese Medicine, Nanning, China.
* Correspondence: Yueping Chen, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, No. 10, Xingning District, Nanning City, Guangxi Zhuang Autonomous Region, People’s Republic of China (e-mail: chenyueping007@126.com).
13 9 2024
13 9 2024
103 37 e3970602 2 2024
19 6 2024
23 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Recent observational studies have indicated that psychiatric disorders were associated with risk of bone mineral density (BMD) reduction. But the causal relationship between neuroticism and BMD remained unclear. By using public genome-wide association study data, a 2-sample bidirectional Mendelian randomization (MR) study was performed to investigate the causal relationship between neuroticism and BMD (heel BMD, forearm BMD, femoral neck BMD, lumbar spine BMD, and total body BMD). Inverse-variance weighted, weighted median, and MR-Egger were used to assess the causal effects. Multiple sensitivity analyses were conducted to assess the potential bias of the causal estimates. Multivariable MR analysis was used to assess the direct causal effects of neuroticism on BMD with adjustment of common risk factors of BMD reduction. Univariable MR analysis indicated that genetically predicted higher neuroticism was significantly associated with an increased risk of heel BMD reduction (inverse-variance weighted β = −0.039; se = 0.01; P = .0001; Bonferroni-corrected P = .0005) but not with other BMD (forearm BMD, femoral neck BMD, lumbar spine BMD, and total body BMD) potentially due to limited statistical power. The causal effects remained significant after accounting for the effects of body mass index, smoking, and drinking. Genetic proxy for higher neuroticism was significantly associated with an increased risk of heel BMD reduction. Further studies were warranted to elucidate the underlying biological mechanisms and explore the potential application in disease early screening and management.

bone mineral density
Mendelian randomization
neuroticism
relationship
Guangxi Key Clinical Specialty (Trauma Surgery) Construction ProjectGuiWeiYiFa {2021}No.17 Not ApplicableGuangxi Key Clinical Specialty (Emergency Medicine) Construction ProjectGuiWeiYiFa {2021}No.8 Not ApplicableClass A Guipai Traditional Chinese Medicine Inheritance Innovation Team of Guangxi University of Chinese medicine2022A004 Not ApplicableGuangxi Xinglin young talents project of Guangxi University of Chinese medicine2022C026 Not ApplicableOPEN-ACCESSTRUE
SDCT
==== Body
pmc1. Introduction

Neuroticism is 1 of the 5 personality traits, and it is typically defined as a persistent tendency toward negative emotional states.[1] Recent studies have shown that there is a significant correlation between neuroticism and mental health.[2] Neuroticism can also be used to predict individuals’ social behavior. People with high neuroticism scores are more likely to communicate emotions such as anxiety and depression and may even display other mental symptoms, social phobia, and substance abuse.[3] Neuroticism is highly inherited, in which 40% to 60% of the phenotypic differences can be explained by genetic factors.[4,5] Neuroticism has been reported to be associated with increased risk of fracture rates and reduced bone mineral density (BMD),[6,7] which is a major basis for clinical diagnosis of osteoporosis. Several studies indicated that psychiatric disorders such as depression,[8] anxiety,[9] and bipolar disorder[10] were closely related to lower BMD.[11,12] Given that neuroticism may trigger psychiatric disorders, especially depression and anxiety,[13,14] we hypothesized that neuroticism may be a potential risk factor for BMD reduction. A recent observational study has also indicated that neurotic people tend to have a higher risk of BMD loss and fracture rate.[15] However, the observational studies were limited by the confounding effects and reverse causality, leaving the causal relationship between neuroticism and BMD unclear.

Mendelian randomization (MR) is a recently developed approach using genetic variants as proxy to test for causal relationships between exposure factors and various disease outcomes.[16,17] MR is based on the principle that alleles are randomly assigned and fixed at conception, which can minimize the bias of confounding factors and reverse causality, thus is conceptually similar to the randomized controlled experiment.[18,19] Previous MR studies have been used to assess the causal effects of neuroticism on multiple diseases, such as cardiovascular cerebrovascular diseases,[20,21] breast cancer,[22] and sarcopenia,[23] but the potential connection between neuroticism and BMD remains unclear. In this study, we used MR to explore the causal relationship between neuroticism and BMD at different sites including total body, forearm, femoral neck, lumbar spine, and heel.

2. Methods

2.1. Study design

In this study, genome-wide association study (GWAS) data from public databases were employed for MR research. Three primary analyses were conducted in this MR study to explore the causal effects of neuroticism on BMD, the causal effects of BMD on neuroticism, direct causal effects of neuroticism on BMD with adjustment of other known risk factors by multivariable MR (MVMR) analysis. In this study, the following 3 fundamental assumptions were utilized to meet the requirements of MR study: there is a robust correlation between genetic instruments and exposure factors; the genetic instruments are not related to any confounding factor concerning exposure-outcome correlation; the genetic instruments can only affect the outcome through their association with exposure (Fig. 1).

Figure 1. MR analysis flowchart. BMD = bone mineral density, BMI = body mass index, IVW = inverse-variance weighted, MR = Mendelian randomization, MVMR = multivariable Mendelian randomization, SNP = single-nucleotide polymorphism, UVMR = univariable Mendelian randomization, WME = weighted median.

2.2. Data sources

The summary statistical data on genetic association with neuroticism for this study were obtained from the UK Biobank. The data set reported a sample of 329,821 unrelated individuals of the European ancestry, all of whom were assessed using the 12-item Eysenck Personality Questionnaire. Age, sex, assessment center, gene sequence, and 40 genetic principal components were used as covariates in the GWAS analysis (Table 1).

Table 1 Data sources.

Name	GWAS ID	Sample size	Race	PMID	Gender	Year	
Neuroticism	ebi-a-GCST005232	329,821	European	29255261	Both	2017	
Forearm BMD	ieu-a-977	8143	European	26367794	Both	2015	
Femoral neck BMD	ieu-a-980	32,735	European	26367794	Both	2015	
Lumbar spine BMD	ieu-a-982	28,498	European	26367794	Both	2015	
Total body BMD	ebi-a-GCST005348	56,284	European	29304378	Both	2018	
Heel BMD	ebi-a-GCST006979	426,824	European	30598549	Both	2019	
BMI	ieu-a-835	322,154	European	25673413	Both	2015	
Drinking	ieu-b-73	335,394	European	30643251	Both	2019	
Smoking	ukb-a-225	336,024	European	30305743	Both	2017	
BMD = bone mineral density, BMI = body mass index, GWAS = genome-wide association study, ID = identity document, PMID = PubMed ID.

BMDs at 5 different sites were explored in the study including total body BMD, forearm BMD, femoral neck BMD, lumbar spine BMD, and heel BMD. The lumbar spine BMD, femoral neck BMD, and forearm BMD GWAS data were obtained from a meta-analysis conducted by Zheng et al,[24] consisting of 28,498, 32,735, and 8143 samples, respectively. GWAS data for the total body BMD were obtained from a meta-analysis by Medina-Gomez et al,[25] including 56,284 samples spanning 15 years of age. Heel bone density GWAS data were collected from the study by Morris et al[26] on the genetic map of osteoporosis effects in humans and mice, which included 426,824 samples.

All samples were of unrelated European descent without sample overlapping. As all the summary-level data are from public databases, there is no need to seek additional ethical application.

2.3. Selection of IVs

Single-nucleotide polymorphisms (SNPs) that are significantly associated with the exposure variables were selected (P < 5.0 × 10−8). Then independent SNPs (R2 < 0.001 in a 10,000-kb window based on the European reference of the 1000 Genomes Project) were selected as genetic instruments for the MR analysis.[27] The F statistic is used to measure the strengths of the instrumental variables. The F value is calculated as F=(n−k−1)k×R21−R2. In this formula, n is the sample size of raw data, k is the number of SNPs in the exposure data, and R2 is the proportion of variants explained by SNPs in the exposure data. All the instruments in the study have F statistics larger than 10, which minimize the risk of weak instrumental bias.

2.4. Univariable MR analysis

To investigate the causal relationship between neuroticism and BMD at different sites, univariable MR analysis was performed using neuroticism as an exposure factor and BMD at different sites as outcomes. The random-effect inverse-variance weighing (IVW) was used as the main method of MR analysis.[28] Besides, in order to ensure the reliability of the causal estimates, additional MR methods (MR-Egger and weighted median [WME]) were adopted to assist in evaluating the final results. MR-Egger applies the inverse of the variance of the outcome as a weight for fitting and considers the presence of an intercept term in the regression. MR-Egger can provide less biased estimation if the final result is influenced by pleiotropy and heterogeneity.[29] In addition, the WME was further employed to assess the final causal effects. WME is the median of a weighted empirical density function defined as a ratio estimate, and consistent causality can be assessed if more than half of the instruments are valid in the analysis.[30] After the forward MR analysis was completed, a univariable reverse MR analysis was performed with BMD at different sites as an exposure and neuroticism as the outcome to assess the reverse causal relationship between neuroticism and BMD at different sites.

Moreover, Cochran Q statistic was used to evaluate the heterogeneity of IVW. MR-Egger intercept test and MR-PRESSO global test analyses were applied to assess the existence of potential horizontal pleiotropy. MR-Egger intercept test allows for non-zero intercepts and is used to detect directional pleiotropy. MR-PRESSO global test is able to detect significant pleiotropy and test on each of the SNPs to identify potential outliers. After removing outliers, we used the remaining SNPs to reestimate the causal effects. The leave-one-out sensitivity test was then applied to evaluate whether the causal effects were driven by specific SNPs. If the following 3 conditions were met, the univariable MR analysis result would be considered as significant: IVW P value is less than the Bonferroni-corrected threshold (P < .05/5 = 0.01); IVW, MR-Egger, and WME had consistent directions of the causal estimates; MR-Egger intercept test and MR-PRESSO global test indicate that there is no evidence of significant horizontal pleiotropy (P > .05).

2.5. MVMR analysis

For the significant causal association identified by the univariable MR analysis, MVMR analysis was used to assess the direct effects of neuroticism on BMD with adjustment of other risk factors for BMD including body mass index (BMI), drinking, and smoking. The multivariable extension of the IVW method was adopted for the MVMR analysis. All the data are analyzed and extracted by the “TwoSampleMR” package in R4.2.0.

2.6. Power analysis

We performed the power analysis using power calculations for MR.[31] The statistical power of detecting the effect size of the IVW method for each MR analysis was reported. The type I error rate α was set to 0.05.

3. Results

3.1. Genetic instrument selection

The causal relationships between neuroticism and BMD at 5 different sites were analyzed utilizing neuroticism as the exposure factor. The number of SNPs used in this study ranged from 55 to 67. The sample size of European descent differed from 8143 to 426,824. All the samples were unrelated to European descent, and there was no sample overlapping. The overall F value for all the instruments was greater than 10 (ranged from 38.51 to 41.70) to minimize the weak instrument bias (Table 2).

Table 2 MR analysis results.

Exposure-outcome	Number of SNPs	F	Method	β	SE	P	
Neuroticism-total body BMD	65	40.94	IVW	−0.039	0.025	.119	
			WME	−0.058	0.034	.087	
			MR-Egger	−0.197	0.176	.267	
Neuroticism-heel BMD	55	38.51	IVW	−0.039	0.010	.0001	
			WME	−0.044	0.012	.0005	
			MR-Egger	−0.029	0.098	.765	
Neuroticism-forearm BMD	67	41.40	IVW	0.087	0.060	.147	
			WME	0.096	0.089	.279	
			MR-Egger	0.388	0.448	.389	
Neuroticism-femoral neck BMD	64	41.70	IVW	−0.011	0.033	.736	
			WME	0.029	0.044	.509	
			MR-Egger	−0.101	0.231	.662	
Neuroticism-lumbar BMD	63	41.65	IVW	−0.023	0.037	.533	
			WME	−0.011	0.050	.815	
			MR-Egger	−0.435	0.256	.095	
BMD = bone mineral density, IVW = inverse-variance weighted, MR = Mendelian randomization, SE = standard error, SNP = single-nucleotide polymorphism, WME = weighted median.

3.2. Bidirectional univariable MR analysis to explore the causal relationship between neuroticism and BMD

Forward univariable MR analysis showed that genetically predicted neuroticism was significantly associated with decreased heel BMD (IVW β = −0.039; SE = 0.01; P = .0001; Bonferroni-corrected P = .0005). MR-Egger (β = −0.029; SE = 0.098; P = .765) and WME (β = −0.044; SE = 0.012; P = .0005) estimates showed similar results (Fig. 2A). Multiple sensitivity analyses were employed to assess the robustness of the significant results. No significant heterogeneity was found for the causal effects of neuroticism on heel BMD (Q = 58.7; P = .16). As for the horizontal pleiotropy, both MR-Egger intercept test (P = .39) and MR-PRESSO global test (P = .17) indicated that the significant causal relationship between neuroticism and heel BMD was unlikely to be biased by the horizontal pleiotropy. The leave-one-out analysis suggested the significant causal relationship was not driven by a specific genetic variant (Fig. 2B). We did not find significant causal effects of neuroticism on BMD at other sites including the forearm, femoral neck, lumbar spine, and total body (Table 2).

Figure 2. Causal effects of neuroticism on heel BMD. (A) Scatter plot. (B) Leave-one-out analysis. BMD = bone mineral density, MR = Mendelian randomization, SNP = single-nucleotide polymorphism.

Furthermore, we explored whether there are any reverse causal effects of BMD on neuroticism by using BMD as an exposure. As indicated in Table S1, Supplemental Digital Content, http://links.lww.com/MD/N581, we did not identify any significant causal effects of BMD on neuroticism.

3.3. Direct causal effects of neuroticism on heel BMD by MVMR analysis

In order to determine whether neuroticism has direct causal effects on heel BMD independent of other risk factors, we further performed MVMR analysis with the adjustment of other common risk factors of BMD. After controlling for the effects of other risk factors, the causal effects of genetically determined neuroticism on heel BMD with the adjustment of BMI (β = −0.082; SE = 0.028; P = .003), drinking (β = −0.066; SE = 0.022; P = .003), smoking (β = −0.055; SE = 0.022; P = .014), and all the factors together (β = −0.097; SE = 0.037; P = .009) remained significant (Table 3).

Table 3 MVMR analysis results.

Exposure-outcome	Outcome	β	SE	P	
Neuroticism + BMI	Heel BMD	−0.082	0.028	.003	
Neuroticism + drinking	Heel BMD	−0.066	0.022	.003	
Neuroticism + smoking	Heel BMD	−0.055	0.022	.014	
Neuroticism + BMI + drinking + smoking	Heel BMD	−0.097	0.037	.009	
BMD = bone mineral density, BMI = body mass index, MVMR = multivariable Mendelian randomization, SE = standard error.

3.4. Power analysis

The post hoc power analysis indicated that there is over 70% power to detect the causal effects of neuroticism on heel BMD, while the power of detecting the causal effects on total body BMD, forearm BMD, femoral neck BMD, and lumbar spine BMD is 15%, 12%, 5.4%, and 6.6%, respectively. Given the sample size of heel BMD is much larger than the other sites (Table 1), the lack of significance at other sites might be due to limited statistical power.

4. Discussion

In this 2-sample MR study, we explored the causal relationship between neuroticism and BMD at different sites by using the summary data of large-scale GWAS summary statistics. The results of this study suggested that genetically determined neuroticism was significantly associated with a lower heel BMD. Moreover, the causal relationship between neuroticism and heel BMD was independent of other known risk factors for BMD by the MVMR analysis. The study provided insights into better understanding of the disease etiology, early intervention, and novel disease management strategies.

Although multiple studies have indicated the impact of mental disorders, especially depression, on BMD and osteoporosis, the causal effects of personality traits such as neuroticism on BMD remained largely unknown. Neuroticism is one of the fundamental personality traits that tend to influence one’s behavior and health in an earlier and more consistent way than the late-onset mental disorders.[32] To the best of our knowledge, this is the first MR study to show a direct causal link between the increased neuroticism levels and decreased BMD. This is consistent with a recent observational study showing that neurotic people tend to have a higher risk of BMD loss and bone fracture.[15] Our MR study helped to show the causal effects of neuroticism on BMD while being less likely to be biased by the confounding factors and reverse causality of the observational studies.

The underlying mechanisms linking neuroticism and BMD remain largely unclear. As neuroticism is highly correlated with the development of mental disorders like depression,[33] while depression and other mood disorders were found to be significantly associated with the BMD reduction and related bone diseases,[34] it is presumed that high neuroticism levels lead to reduced BMD through triggering the development of mental disorders such as depression and anxiety. On the other hand, neuroticism has been found to be associated with elevated inflammation and might lead to increased levels of proinflammatory molecules.[35] Numerous studies have found a shift toward an active immune profile was implicated in the development of osteoporosis.[36,37] Therefore, the chronic inflammation induced by neuroticism might be another potential mechanism underlying the causal relationship between neuroticism and BMD. Further studies were warranted to elucidate the underlying biological mechanisms between neuroticism and BMD.

Recent studies have shown that people who suffer from negative emotions for a long time often have unhealthy behaviors such as smoking and drinking. In addition, previous MR study results show that BMI, smoking, and drinking have causal relationships with BMD in different parts and are risk factors.[38,39] The causal association remained significant after adjusting for the effects of BMI, drinking, and smoking. This suggests that neuroticism is an independent and unreported risk factor for decreased BMD, similar to other known risk factors such as smoking, alcohol consumption, BMI, low calcium intake, and perimenopause.

There are several limitations of the study worth mentioning. First, the GWAS data included in this study for MR analysis were all from European populations, so the results of the study may not be applicable to other populations. Subsequent studies in other ethnic groups are needed to validate the findings in other ethnic groups. Second, although we have conducted extensive sensitivity analyses to minimize the potential bias, the MR analysis in nature was impossible to rule out all the bias, especially the horizontal pleiotropy. The results need to be interpreted with caution, especially the potential clinical applications. Third, due to the availability of the GWAS data, we have limited power to detect the causal effects at other BMDs (forearm BMD, femoral neck BMD, lumbar spine BMD, and total body BMD) except heel BMD. Future studies with larger sample size were warranted to examine the causal effects of neuroticism on BMD across different sites.

5. Conclusions

Genetic proxy for higher neuroticism was significantly associated with an increased risk of heel BMD reduction. Further studies were warranted to elucidate the underlying biological mechanisms and explore the potential application in disease early screening and management.

Author contributions

Conceptualization: Shangtong Chen, Jing Zhong, Yueping Chen.

Data curation: Shangtong Chen, Jing Zhong.

Formal analysis: Shangtong Chen, Jing Zhong, Xiaoyun Zhang, Feng Chen, Chuanhong Huang.

Methodology: Shangtong Chen, Jing Zhong, Yueping Chen, Xiaoyun Zhang.

Writing – original draft: Shangtong Chen, Jing Zhong.

Writing – review & editing: Shangtong Chen, Jing Zhong, Yueping Chen.

Supervision: Yueping Chen.

Validation: Yueping Chen.

Investigation: Xiaoyun Zhang, Feng Chen, Chuanhong Huang.

Project administration: Xiaoyun Zhang, Feng Chen, Chuanhong Huang.

Software: Feng Chen.

Visualization: Chuanhong Huang.

Supplementary Material

Abbreviations:

BMD bone mineral density

BMI body mass index

GWAS genome-wide association study

IVW inverse-variance weighted

MR Mendelian randomization

MVMR multivariable Mendelian randomization

SNP single-nucleotide polymorphism

WME weighted median

This work was supported by the Guangxi Key Clinical Specialty (Trauma Surgery) Construction Project (GuiWeiYiFa No. 17); Guangxi Key Clinical Specialty (Emergency Medicine) Construction Project (GuiWeiYiFa No. 8); Class A Guipai Traditional Chinese Medicine Inheritance Innovation Team of Guangxi University of Chinese Medicine (2022A004); Guangxi Xinglin Young Talents Project of Guangxi University of Chinese Medicine (2022C026).

All analyses were based on previous published studies, thus no ethical approval and patient consent are required.

The authors have no conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Supplemental Digital Content is available for this article.

How to cite this article: Chen S, Zhong J, Chen Y, Zhang X, Huang C, Chen F. Causal relationship between neuroticism and bone mineral density: A univariable and multivariable Mendelian randomization study. Medicine 2024;103:37(e39706).

SC and JZ contributed to this article equally.
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