Causal relationship between atrial fibrillation and cognitive impairment: a Mendelian randomization study

doi:10.3969/j.issn.1674-8115.2023.11.003

Abstract

Abstract:

Objective ·To investigate the causal relationship between atrial fibrillation (AF) and cognitive impairment. Methods ·A two-sample Mendelian randomization (TSMR) analysis was used to assess the potential causality of AF on cognitive dysfunction. Single nucleotide polymorphisms (SNPs) strongly associated with AF were extracted as instrumental variables by using a dataset of a large-scale genome-wide association study (GWAS) on AF. The associations of SNPs with Alzheimer′s disease dementia, Parkinson′s disease dementia, vascular dementia, Lewy body dementia, frontotemporal dementia, undefined dementia, and overall cognitive function assessment were extracted separately from publicly available GWAS data on cognitive dysfunction. The inverse variance-weighted (IVW) method was used for the main analysis, and sensitivity analyses were conducted by using Cochran′s Q test, MR-Egger regression, and leave-one-out method. To verify the robustness of the results, replicate analyses and meta-analyses were performed by using different GWAS data. Results ·In the initial analysis, 101 SNPs were extracted as instrumental variables from a meta-analysis of a genome-wide association study involving up to 1 030 836 individuals. The IVW analysis showed no evidence for causal associations between AF and dementia [dementia (OR=1.032; 95%CI 0.973?1.094; P=0.290), Parkinson′s disease dementia (OR=1.004; 95%CI 0.780?1.291; P=0.977), vascular dementia (OR=1.123; 95%CI 0.969?1.301; P=0.125), or unspecified dementia (OR=1.013; 95%CI 0.910?1.129; P=0.807)]. In the replication analysis, 27 SNPs were extracted as instrumental variables from the FinnGen AF GWAS data, and the IVW analysis were consistent with the initial analysis [cognitive function (OR=0.999; 95%CI 0.982?1.016; P=0.874), Alzheimer′s disease dementia (OR=0.977; 95%CI 0.943?1.012; P=0.193), Lewy body dementia (OR=1.014; 95%CI 0.898?1.145; P=0.826), or frontotemporal dementia (OR=0.996; 95%CI 0.745?1.333; P=0.980)]. Both Mendelian randomization analyses and meta-analyses showed no evidence of an association between genetically predicted AF and different types of dementia or overall cognitive function assessment. MR-Egger regression suggested no horizontal pleiotropy and leave-one-out analysis showed stable results after individually removing each SNP. Conclusion ·No evidence of a causal relationship between AF and cognitive impairment was found. The associations observed in observational studies can be partially attributed to confounding factors such as shared biology or co-morbidities.

Key words: atrial fibrillation, cognitive dysfunction, causality, genetics, Mendelian randomization study

CLC Number:

R541

GAO Xiong, ZHANG Qiuxia, YANG Miaomiao, LUO Wei, WANG Yuegang, XIU Jiancheng. Causal relationship between atrial fibrillation and cognitive impairment: a Mendelian randomization study[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(11): 1359-1365.

Figures/Tables 6

TrendMD

References 32

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Analysis	Exposure	ID	Sample size/n	Race	Year	PMID
First analysis	Atrial fibrillation	ebi-a-GCST006414	1 030 836	European	2018	30061737
Duplicate analysis	Atrial fibrillation	finn-b-I9	138 994	European	2021	NA

Analysis	Exposure	ID	Sample size/n	Race	Year	PMID
First analysis	Atrial fibrillation	ebi-a-GCST006414	1 030 836	European	2018	30061737
Duplicate analysis	Atrial fibrillation	finn-b-I9	138 994	European	2021	NA

Analysis	Outcome	ID	Sample size/n	Race	Year	PMID
First analysis	Dementia	finn-b-F5_DEMENTIA	216 771	European	2021	NA
First analysis	Dementia due to Parkinson′s disease	finn-b-PD_DEMENTIA	216 895	European	2021	NA
First analysis	Vascular dementia	finn-b-F5_VASCDEM	212 389	European	2021	NA
First analysis	Undefined dementia	finn-b-F5_Dementia_U	215 511	European	2021	NA
Duplicate analysis	Cognitive performance	ebi-a-GCST006572	257 841	European	2018	30038396
Duplicate analysis	Alzheimer′s disease	ebi-a-GCST90012877	472 868	European	2021	33589840
Duplicate analysis	Dementia with Lewy body	ebi-a-GCST90001390	6 618	European	2021	33589841
Duplicate analysis	Rontotemporal dementia	ieu-b-43	3 024	European	2010	20154673

Analysis	Outcome	ID	Sample size/n	Race	Year	PMID
First analysis	Dementia	finn-b-F5_DEMENTIA	216 771	European	2021	NA
First analysis	Dementia due to Parkinson′s disease	finn-b-PD_DEMENTIA	216 895	European	2021	NA
First analysis	Vascular dementia	finn-b-F5_VASCDEM	212 389	European	2021	NA
First analysis	Undefined dementia	finn-b-F5_Dementia_U	215 511	European	2021	NA
Duplicate analysis	Cognitive performance	ebi-a-GCST006572	257 841	European	2018	30038396
Duplicate analysis	Alzheimer′s disease	ebi-a-GCST90012877	472 868	European	2021	33589840
Duplicate analysis	Dementia with Lewy body	ebi-a-GCST90001390	6 618	European	2021	33589841
Duplicate analysis	Rontotemporal dementia	ieu-b-43	3 024	European	2010	20154673

Analysis	Outcome	IVW method		WM method		MR-Egger method
Analysis	Outcome	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value
First analysis	Dementia	1.032 (0.973‒1.094)	0.290	1.020 (0.920‒1.131)	0.703	1.077 (0.962‒1.206)	0.203
First analysis	Dementia due to Parkinson′s disease	1.004 (0.780‒1.291)	0.977	0.795 (0.508‒1.245)	0.316	0.982 (0.603‒1.597)	0.941
First analysis	Vascular dementia	1.123 (0.969‒1.301)	0.125	1.180 (0.898‒1.550)	0.234	1.260 (0.947‒1.676)	0.116
First analysis	Undefined dementia	1.013 (0.910‒1.129)	0.807	1.053 (0.862‒1.285)	0.615	1.170 (0.951‒1.441)	0.142
Duplicate analysis	Cognitive performance	0.999 (0.982‒1.016)	0.874	0.989 (0.975‒1.004)	0.168	0.983 (0.946‒1.022)	0.405
Duplicate analysis	Alzheimer′s disease	0.977 (0.943‒1.012)	0.193	0.976 (0.930‒1.024)	0.324	0.994 (0.915‒1.079)	0.885
Duplicate analysis	Dementia with Lewy body	1.014 (0.898‒1.145)	0.826	1.106 (0.932‒1.311)	0.248	1.253 (0.953‒1.647)	0.120
Duplicate analysis	Rontotemporal dementia	0.996 (0.745‒1.333)	0.980	0.966 (0.666‒1.399)	0.853	0.874 (0.480‒1.590)	0.672