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

Abstract

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

CLC Number:

R749.16

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.

Figures/Tables 7

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References 32

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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

Causal relationship between tinnitus and risk of Alzheimer’s disease analyzed by Mendelian randomization

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