孤独、主观幸福感与衰弱指数因果关系的孟德尔随机化研究

doi:10.3969/j.issn.1674-8115.2026.01.009

上海交通大学学报（医学版） ›› 2026, Vol. 46 ›› Issue (1): 75-81.doi: 10.3969/j.issn.1674-8115.2026.01.009

孤独、主观幸福感与衰弱指数因果关系的孟德尔随机化研究

艾克热木·艾尔肯¹, 陈兴娟², 钮岳岳²()

^1.新疆维吾尔自治区人民医院中西医协同诊疗医学中心，乌鲁木齐 830054
^2.中国中医科学院广安门医院干保科，北京 100053

收稿日期:2025-05-16 接受日期:2025-10-20 出版日期:2026-01-28 发布日期:2026-01-30
通讯作者: 钮岳岳，住院医师，博士；电子信箱：952830794@qq.com。
作者简介:第一联系人：艾克热木·艾尔肯负责研究设计、统计分析并撰写论文初稿，陈兴娟负责数据收集，钮岳岳负责论文审阅及修订。所有作者均阅读并同意了最终稿件的提交。
基金资助:
中央高水平中医医院临床研究和成果转化能力提升项目(HLCMHPP2023079)

Mendelian randomization study of loneliness, subjective well-being, and frailty index

Aikeremu Aierken¹, Chen Xingjuan², Niu Yueyue²()

^1.Chinese and Western Medicine Collaborative Diagnosis and Treatment Medical Center, People′s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830054, China
^2.Cadres Health Protection Department, Guang′anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China

Received:2025-05-16 Accepted:2025-10-20 Online:2026-01-28 Published:2026-01-30
Contact: Niu Yueyue, E-mail: 952830794@qq.com.
About author:First author contact:Aierken Aikeremu was responsible for the research design and the statistical analysis, and drafted the initial manuscript. Chen Xingjuan was responsible for data collection. Niu Yueyue reviewed and revised the manuscript. All authors have read the final version of manuscript and consented to its submission.
Supported by:
High Level Chinese Medical Hospital Promotion Project(HLCMHPP2023079)

摘要/Abstract

摘要：

目的·采用双样本孟德尔随机化（Mendelian randomization，MR）方法验证孤独、主观幸福感与衰弱指数的关联是否反映了因果关系。方法·基于已发表的全基因组关联研究（genome-wide association studies，GWAS）的摘要数据，利用MR方法分析孤独感、主观幸福感与衰弱指数（作为衰弱的替代指标）的因果关系。孤独感数据来源于包含445 024名欧洲血统参与者的研究，包括80 134名欧洲血统病例和364 890名欧洲血统对照；主观幸福感数据来自298 420名欧洲血统参与者；衰弱的汇总数据来自英国生物银行和瑞典TwinGene GWAS的meta分析，包括175 226名欧洲血统的参与者。使用逆方差加权（inverse variance weighted，IVW）方法作为主要的MR分析方法确定估计值，加权中位数（weighted median estimator，WME）作为补充方法。采用Cochran′s Q检验检查IVW估计值中异质性，并使用MR Egger截距检验指示多效性的存在。存在异质性时使用异常值全局检测MR-PRESSO识别离群值，去除离群值后，重复MR分析。进行留一分析，以评估总体估计值是否由单一的单核苷酸多态性（single nucleotide polymorphism，SNP）驱动。在暴露和结局数据的效应方向校正过程中，剔除等位基因方向难以确定的回文SNP以确保数据的一致性和分析的可靠性。结果·通过IVW证实孤独感与衰弱指数呈显著正相关，OR为3.87（95% CI 2.33~6.46，P<0.001）；WME进一步验证了这一结果，OR为2.81（95% CI 1.49~5.29，P<0.001）。主观幸福感与衰弱指数呈显著负相关，OR为0.80（95% CI 0.69~0.94，P=0.005）；WME结果趋势一致，OR为0.86（95% CI 0.74~1.01，P=0.065）。未发现异质性（Cochran′s Q检验，P=0.054和P=0.074）或水平多效性（MR-Egger截距检验，P=0.470和P=0.260）。结论·通过MR方法强化了孤独感增加衰弱风险、主观幸福感对衰弱具有保护作用的因果证据。

关键词: 孟德尔随机化, 孤独感, 主观幸福感, 衰弱指数, 因果推断

Abstract:

Objective ·To employ a two-sample Mendelian randomization (MR) design to examine whether the associations between loneliness, subjective well-being, and the frailty index reflect causal relationships. Methods ·Summary data from published genome-wide association studies (GWAS) were utilized, and an MR approach was employed to analyze the causal relationships between loneliness, subjective well-being, and the frailty index (as a surrogate measure of frailty). Data on loneliness were derived from a study comprising 445 024 individuals of European ancestry, including 80 134 cases and 364 890 controls. Data for subjective well-being were obtained from 298 420 participants of European ancestry. Summary statistics for frailty were sourced from a meta-analysis of GWAS conducted within the UK Biobank and the Swedish TwinGene cohort, which included 175 226 individuals of European ancestry. The inverse variance weighted (IVW) method served as the primary MR analytical approach to derive causal estimates, with the weighted median estimator (WME) used as a supplementary approach. Cochran′s Q test was applied to assess heterogeneity in the IVW estimates. The presence of horizontal pleiotropy was evaluated using the MR-Egger intercept test. When significant heterogeneity was detected, the MR-PRESSO global test was utilized to identify and subsequently remove outlier variants. MR analyses were then repeated. A Leave-One-Out sensitivity analysis was conducted to evaluate whether the overall estimates were unduly influenced by any single nucleotide polymorphism (SNP). To ensure data consistency and analytical reliability during effect allele harmonization between exposure and outcome datasets, palindromic SNPs (for which the effect allele direction could not be definitively determined) were excluded. Results ·The IVW method revealed a significant positive association between loneliness and the frailty index, with an OR of 3.87 (95% CI 2.33‒6.46, P<0.001). This result was further confirmed by the WME, yielding an OR of 2.81 (95% CI 1.49‒5.29, P<0.001). Subjective well-being showed a significant negative association with the frailty index (OR=0.80, 95% CI 0.69‒0.94, P=0.005). The WME demonstrated a consistent direction of effect, though with borderline significance (OR=0.86, 95% CI 0.74‒1.01, P=0.065). The analysis revealed no significant heterogeneity (Cochran′s Q test, P=0.054 and P=0.074) or horizontal pleiotropy (MR-Egger intercept test, P=0.470 and P=0.260). Conclusion ·This study, supported by the MR methodology, indicates that loneliness is associated with an increased risk of frailty, while subjective well-being serves as a protective factor against frailty.

Key words: Mendelian randomization (MR), loneliness, subjective well-being, frailty index, causal inference

中图分类号:

R212.7

艾克热木·艾尔肯, 陈兴娟, 钮岳岳. 孤独、主观幸福感与衰弱指数因果关系的孟德尔随机化研究[J]. 上海交通大学学报（医学版）, 2026, 46(1): 75-81.

Aikeremu Aierken, Chen Xingjuan, Niu Yueyue. Mendelian randomization study of loneliness, subjective well-being, and frailty index[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(1): 75-81.

图/表 8

参考文献 40

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SNP	EA	NEA	EAF	β	SE	P value	F statistics
rs6430286	G	A	0.58	0.005	0.001	1.44×10^-8	32.14
rs74338595	T	C	0.71	0.005	0.001	4.82×10^-9	34.26
rs4465966	A	G	0.43	0.005	0.001	1.44×10^-8	32.13
rs171697	C	G	0.67	-0.005	0.001	6.81×10^-9	33.59
rs2069117	A	C	0.37	-0.005	0.001	8.97×10^-10	37.54
rs10456089	G	A	0.92	0.009	0.002	2.55×10^-9	35.50
rs7770860	T	C	0.63	-0.005	0.001	1.45×10^-8	32.12
rs773020	G	A	0.10	-0.009	0.001	5.32×10^-9	34.07
rs13291079	T	C	0.58	0.005	0.001	9.21×10^-11	41.99
rs62085660	C	G	0.26	0.005	0.001	4.86×10^-9	34.24
rs613872	G	T	0.17	-0.008	0.001	5.77×10^-14	56.45

SNP	EA	NEA	EAF	β	SE	P value	F statistics
rs6430286	G	A	0.58	0.005	0.001	1.44×10^-8	32.14
rs74338595	T	C	0.71	0.005	0.001	4.82×10^-9	34.26
rs4465966	A	G	0.43	0.005	0.001	1.44×10^-8	32.13
rs171697	C	G	0.67	-0.005	0.001	6.81×10^-9	33.59
rs2069117	A	C	0.37	-0.005	0.001	8.97×10^-10	37.54
rs10456089	G	A	0.92	0.009	0.002	2.55×10^-9	35.50
rs7770860	T	C	0.63	-0.005	0.001	1.45×10^-8	32.12
rs773020	G	A	0.10	-0.009	0.001	5.32×10^-9	34.07
rs13291079	T	C	0.58	0.005	0.001	9.21×10^-11	41.99
rs62085660	C	G	0.26	0.005	0.001	4.86×10^-9	34.24
rs613872	G	T	0.17	-0.008	0.001	5.77×10^-14	56.45

SNP	EA	NEA	EAF	β	SE	P value	F statistics
rs10484399	A	G	0.916 04	-0.026	0.005	1.99×10^-7	27.04
rs10769190	T	C	0.197 80	0.018	0.004	6.80×10^-6	20.25
rs11073619	T	C	0.104 50	0.025	0.005	5.73×10^-7	25.00
rs11610143	C	G	0.802 20	0.019	0.004	2.03×10^-6	22.56
rs12143280	T	C	0.944 03	0.038	0.008	2.03×10^-6	22.56
rs12298541	A	C	0.356 30	0.016	0.003	9.64×10^-8	28.44
rs13235506	T	G	0.955 22	-0.034	0.007	1.19×10^-6	23.59
rs17005492	T	C	0.785 40	0.018	0.004	6.80×10^-6	20.25
rs2017279	A	G	0.679 10	0.016	0.003	9.64×10^-8	28.44
rs258668	T	C	0.595 10	-0.017	0.003	1.46×10^-8	32.11
rs4589952	T	C	0.154 90	-0.021	0.004	1.52×10^-7	27.56
rs6587766	T	C	0.041 04	0.047	0.009	1.77×10^-7	27.27
rs707533	A	G	0.666 00	0.019	0.003	2.40×10^-10	40.11
rs7149000	A	G	0.459 00	-0.014	0.003	3.06×10^-6	21.78
rs7239568	A	C	0.688 40	-0.016	0.003	9.64×10^-8	28.44
rs7969982	T	C	0.925 37	-0.031	0.006	2.38×10^-7	26.69

SNP	EA	NEA	EAF	β	SE	P value	F statistics
rs10484399	A	G	0.916 04	-0.026	0.005	1.99×10^-7	27.04
rs10769190	T	C	0.197 80	0.018	0.004	6.80×10^-6	20.25
rs11073619	T	C	0.104 50	0.025	0.005	5.73×10^-7	25.00
rs11610143	C	G	0.802 20	0.019	0.004	2.03×10^-6	22.56
rs12143280	T	C	0.944 03	0.038	0.008	2.03×10^-6	22.56
rs12298541	A	C	0.356 30	0.016	0.003	9.64×10^-8	28.44
rs13235506	T	G	0.955 22	-0.034	0.007	1.19×10^-6	23.59
rs17005492	T	C	0.785 40	0.018	0.004	6.80×10^-6	20.25
rs2017279	A	G	0.679 10	0.016	0.003	9.64×10^-8	28.44
rs258668	T	C	0.595 10	-0.017	0.003	1.46×10^-8	32.11
rs4589952	T	C	0.154 90	-0.021	0.004	1.52×10^-7	27.56
rs6587766	T	C	0.041 04	0.047	0.009	1.77×10^-7	27.27
rs707533	A	G	0.666 00	0.019	0.003	2.40×10^-10	40.11
rs7149000	A	G	0.459 00	-0.014	0.003	3.06×10^-6	21.78
rs7239568	A	C	0.688 40	-0.016	0.003	9.64×10^-8	28.44
rs7969982	T	C	0.925 37	-0.031	0.006	2.38×10^-7	26.69

孤独、主观幸福感与衰弱指数因果关系的孟德尔随机化研究

Mendelian randomization study of loneliness, subjective well-being, and frailty index

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Metrics

Phenotype	Sample size/n	Case/n	Control/n	Year	PubMed ID	Population
Exposure phenotype
Loneliness	445 024	80 134	364 890	2018	29970889	European
Subjective well-being	298 420			2016	27089181	European
Outcome phenotype (frailty index)	175 226			2021	34431594	European

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