基于耳鸣与阿尔茨海默病发病风险因果关系的孟德尔随机化分析

doi:10.13481/j.1671-587X.20250421

摘要/Abstract

摘要：

目的采用两样本孟德尔随机化（MR）方法评估耳鸣与阿尔茨海默病（AD）发病风险之间的潜在因果关系，并阐明其作用机制，为AD早期预警提供新思路。方法利用全基因组关联研究（GWAS）数据库，搜索关键词“tinnitus”和“Alzheimer”，获取暴露因素耳鸣和结局AD的相关数据集，其中耳鸣数据集包括ukb-d-4803_11、ukb-d-4803_12、ukb-d-4803_13、ukb-b-14254和ukb-a-384，AD数据集包括ieu-b-5067、ieu-b-2、ieu-a-297、ebi-a-GCST90027158和ebi-a-GCST002245。筛选与耳鸣密切相关且独立的单核苷酸多态性（SNPs）作为工具变量（IVs），与AD相关的SNPs作为结局。采用逆方差加权法（IVW）进行MR分析，评估其比值比（OR）值、95%置信区间（CI）及P值，当P<0.05时提示存在显著因果关系。敏感性检测使用Cochran’s Q检验IVs的异质性，评估其Q值、df值和P值，当IVW分析法的P>0.05时，提示无显著异质性；采用MR-Egger截距检测水平多效性，当截距为0或接近0，且P>0.05时，提示无显著水平多效性；采用留一法进行敏感性分析，通过森林图、散点图、漏斗图和留一图进行结果可视化。结果共筛选出286个SNPs作为IVs。所有的IVs满足F>10，提示不存在弱IVs，经过PhenoScanner网页工具筛选，所有SNPs与混杂因素无关。当耳鸣和AD数据集分别为ukb-d-4803和ebi-a-GCST90027158时，耳鸣与AD发病风险之间呈显著正相关关系（OR=1.842，95%CI=1.065~3.188，P=0.029）；Cochran’s Q检验提示IVs不存在显著异质性（Q=9.788，df=10.000，P=0.459）；MR-Egger截距表明无水平多效性（Egger intercept=-0.006，P=0.147）；留一法显示结果稳定，未检测出对结果影响大的SNPs。结论耳鸣与AD的发病风险之间存在正向因果关系。神经炎症伴随不同程度的小胶质细胞持续激活，可能是耳鸣与AD的共同发病机制。抑郁症也可能作为上游因素，过度激活了下丘脑-垂体-肾上腺（HPA）轴，从而导致耳鸣与AD关系的进阶。

关键词: 耳鸣, 阿尔茨海默病, 孟德尔随机化, 全基因组关联研究, 逆方差加权法

Abstract:

Objective To evaluate the potential causal relationship between tinnitus and the risk of Alzheimer’s disease （AD） onset using the two-sample Mendelian randomization （MR） method and to clarify its mechanism of action， so as to provide new ideas for early warning of AD. Methods Genome-wide association study （GWAS） database was used to search the keywords “tinnitus” and “Alzheimer” to obtain the related datasets of exposure factor tinnitus and outcome AD； the tinnitus datasets included ukb-d-4803_11， ukb-d-4803_12， ukb-d-4803_13， ukb-b-14254 and ukb-a-384； the AD datasets included ieu-b-5067， ieu-b-2， ieu-a-297， ebi-a-GCST90027158 and ebi-a-GCST002245. The single nucleotide polymorphisms （SNPs） closely and independently associated with tinnitus were screened as instrumental variables （IVs）， and the SNPs associated with AD were used as outcomes. Inverse variance weighted （IVW） method was used to conduct MR analysis to evaluate its odds ratio （OR） value， 95% confidence interval （CI） and P value； P<0.05 indicated significant causal relationship. Sensitivity detection used Cochran’s Q test to detect the heterogeneity of IVs to evaluate its Q value， df value and P value； when IVW method P>0.05， it indicated no significant heterogeneity； MR-Egger intercept was used to detect horizontal pleiotropy； when the intercept was 0 or close to 0 and P>0.05， it indicated no significant horizontal pleiotropy； meanwhile， leave-one-out method was used for sensitivity analysis. Finally， visualization results were performed using forest plot， scatter plot， funnel plot and leave-one-out plot. Results A total of 286 SNPs were screened as IVs. All instrumental variables satisfied F>10， suggesting no weak instrumental variable； after screening by PhenoScanner web tool， all SNPs were unrelated to confounding factors. When the tinnitus and AD datasets were ukb-d-4803 and ebi-a-GCST90027158 respectively， there was a significant positive correlation between tinnitus and the risk of AD onset （IVW： OR=1.842， 95%CI：1.065-3.188， P=0.029）； Cochran’s Q test suggested no significant heterogeneity of IVs （Q=9.788， df=10.000， P=0.459）； MR-Egger intercept indicated no horizontal pleiotropy （Egger intercept=-0.006， P=0.147）； leave-one-out method showed stable results， and no SNP with significant influence on the results was detected. Conclusion There is a positive causal relationship between tinnitus and the risk of AD onset. Neuroinflammation accompanied by persistent microglial activation to varying degrees may be the common pathogenesis of tinnitus and AD； in addition， depression may also act as an upstream factor to hyperactivate the hypothalamic-pituitary-adrenal （HPA） axis， leading to the progression of relationship between tinnitus and AD.

Key words: Tinnitus, Alzheimer disease, Mendelian randomization, Genome-wide association study, Inverse variance weighted method

中图分类号:

R749.16

孙行云,李傅尧,李可心,时晶. 基于耳鸣与阿尔茨海默病发病风险因果关系的孟德尔随机化分析[J]. 吉林大学学报(医学版), 2025, 51(4): 1052-1060.

Xingyun SUN,Fuyao LI,Kexin LI,Jing SHI. Causal relationship between tinnitus and risk of Alzheimer’s disease analyzed by Mendelian randomization[J]. Journal of Jilin University(Medicine Edition), 2025, 51(4): 1052-1060.

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ID	Year	Trait	Sample Size	Number of SNPs	Population	Gender
ukb-d-4803_11	2018	Tinnitus: Yes, now most or all of the time	117 882	12 817 923	European	Males and females
ukb-d-4803_12	2018	Tinnitus: Yes, now a lot of the time	117 882	11 127 194	European	Males and females
ukb-d-4803_13	2018	Tinnitus: Yes, now some of the time	117 882	11 127 194	European	Males and females
ukb-b-14254	2018	Tinnitus severity/nuisance	43 349	9 851 867	European	Males and females
ukb-a-384	2017	Tinnitus: Yes now some of the time	109 411	10 894 596	European	Males and females
ieu-b-5067	2022	AD	488 285	12 321 875	European	Males and females
ieu-b-2	2019	AD	63 926	10 528 610	European	Males and females
ieu-a-297	2013	AD	54 162	7 055 882	European	Males and females
ebi-a-GCST90027158	2022	AD	487 511	20 921 626	European	Males and females
ebi-a-GCST002245	2013	AD	55 134	7 022 150	European	Males and females

Tinnitus	AD	Cochran’s Q (IVW)			MR-Egger
Tinnitus	AD	Q	df	P	Intercept	P
pukb-d-4803	ieu-b-5067	46.299	42.000	0.299	<0.05	0.723
	ieu-b-2	46.299	42.000	0.299	0.007	0.403
	ieu-a-297	28.813	29.000	0.475	0.011	0.272
	ebi-a-GCST90027158	44.990	39.000	0.235	-0.006	0.147
	ebi-a-GCST002245	28.835	30.000	0.526	0.011	0.268
ukb-b-14254	ieu-b-5067	12.810	11.000	0.306	<0.05	0.625
	ieu-b-2	11.515	10.000	0.319	-0.012	0.482
	ieu-a-297	16.463	10.000	0.087	-0.007	0.777
	ebi-a-GCST90027158	6.037	11.000	0.871	-0.011	0.196
	ebi-a-GCST002245	16.463	10.000	0.087	-0.007	0.777
ukb-a-384	ieu-b-5067	13.529	10.000	0.196	<0.05	0.585
	ieu-b-2	7.187	10.000	0.708	-0.035	0.192
	ieu-a-297	10.420	7.000	0.166	-0.046	0.274
	ebi-a-GCST90027158	9.788	10.000	0.459	-0.026	0.079
	ebi-a-GCST002245	10.420	7.000	0.166	-0.046	0.274