Causal relationship of genetically predicted particulate matter 2.5 level with Alzheimer’s disease and the mediating effect of dehydroepiandrosterone sulphate

Figures & data

Figure 1. Overview of the Mendelian randomisation design.

The solid lines represent meaningful pathways, and the dashed lines represent nonexistent pathways in Mendelian randomisation analysis.

Table 1. Summary of the included traits in the Mendelian randomisation study.

ID	Trait	Author	Consortium	Date source	Population	Sample	SNPs	Year
Expose
ukb-b-10817	PM 2.5	Ben Elsworth	MRC-IEU	UK Biobank	European	423796	9851867	2018
Mediator
ebi-a-GCST004941	Dehydroepiandrosterone sulphate levels	Prins BP	NA	EBI GWAS database	European	9722	21770677	2017
Outcome
ieu-a-297	Alzheimer’s disease	Lambert	IGAP	IEU OpenGWAS database	European	54162	7055882	2013

PM: particulate matter; SNP: single-nucleotide polymorphism; NA: not available.

Table 2. Detailed information on genetic instruments associated with Alzheimer’s disease.

Exposure	SNP	SE	β	EAF	P-value	F_statistic	R^2
Dehydroepiandrosterone sulphate levels	rs604126	0.010	0.050	NA	1.110E-08	25.000	2.565E-03
Dehydroepiandrosterone sulphate levels	rs1105977	0.010	0.050	NA	1.064E-08	25.000	2.565E-03
Dehydroepiandrosterone sulphate levels	rs148982377	0.020	−0.340	NA	2.273E-60	289.000	2.887E-02
Dehydroepiandrosterone sulphate levels	rs2911280	0.020	−0.090	NA	2.253E-08	20.250	2.079E-03
PM 2.5	rs6749467	0.002	−0.012	0.466	1.400E-08	32.228	7.604E-05
PM 2.5	rs1372504	0.002	0.012	0.374	3.100E-08	30.674	7.237E-05
PM 2.5	rs12203592	0.003	0.022	0.213	6.200E-17	69.918	1.650E-04
PM 2.5	rs77255816	0.006	0.031	0.037	4.200E-08	30.041	7.088E-05
PM 2.5	rs77205736	0.002	0.014	0.274	2.100E-08	31.399	7.408E-05
PM 2.5	rs1537371	0.002	0.012	0.500	8.500E-09	33.149	7.821E-05

PM: particulate matter; SNP: single-nucleotide polymorphism; NA: not available; EAF: effect allele frequency; SE: standard error.

Figure 2. Association of the genetically determined PM2.5 and dehydroepiandrosterone sulphate with Alzheimer’s disease.

CI: confidence interval; OR: odds ratio; PM: particulate matter; DHEAS: dehydroepiandrosterone sulphate; MR-PRESSO: Mendelian randomisation pleiotropy residual sum and outlie; MVMR: multivariable Mendelian randomisation.

Figure 3. Forest plot of PM2.5 and dehydroepiandrosterone sulphate associated with risk of Alzheimer’s disease. The x-axis showed the MR effect size for PM2.5 and dehydroepiandrosterone sulphate on Alzheimer’s disease: (A)PM 2.5, (B) dehydroepiandrosterone sulphate. The y-axis showed the analysis for each of the SNPs.

PM: particulate matter; SNP: single nucleotide polymorphism; MR: Mendelian randomisation.

Table 3. Mendelian randomisation assessing the causal association between expose/mediator and Alzheimer’s disease.

						Heterogeneity		Pleiotropy
Exposure	Outcome	SNPs	Method	OR(95% CI)	P-value	Q statistic	P-value	Intercept	P-value
Dehydroepiandrosterone sulphate levels	Alzheimer’s disease	4	MR Egger	0.73(0.53,1.01)	0.198	0.327	0.849	0.0014	0.941
		4	Weighted median	0.734(0.57,0.95)	0.0167
		4	Inverse variance weighted	0.738(0.59,0.92)	0.00754	0.334	0.953
		4	Simple mode	0.687(0.48,0.99)	0.134
		4	Weighted mode	0.736(0.56,0.97)	0.118
PM 2.5	Alzheimer’s disease	6	MR Egger	3.88(0.09,166)	0.518	3.640	0.457	−0.0045	0.879
		6	Weighted median	3.21(0.86,12.0)	0.0825
		6	Inverse variance weighted	2.88(1.01,8.18)	0.0475	3.670	0.598
		6	Simple mode	5.78(0.71,47.20)	0.162
		6	Weighted mode	5.54(0.65,47.40)	0.179
PM 2.5	Dehydroepiandrosterone sulphate levels	6	MR Egger	1.26(0.418,3.78)	0.705	0.611	0.962	0.0086	0.453
		6	Weighted median	2.20(1.16,4.16)	0.016
		6	Inverse variance weighted	1.90(1.14,3.17)	0.014	1.301	0.935
		6	Simple mode	2.25(0.90,5.59)	0.143
		6	Weighted mode	2.37(0.93,6.07)	0.132

PM: particulate matter; SNP: single-nucleotide polymorphism; CI: confidence interval; OR: odds ratio; MR: Mendelian randomisation.

Table 4. Mediation analysis of the mediation effect of PM2.5 on Alzheimer’s disease via dehydroepiandrosterone sulphate levels.

Mediator	Total effect	Direct effect A	Direct effect B	Mediation effect	Mediated proportion%
	β (95% CI)	β (95% CI)	β (95% CI)	β (95% CI)
Dehydroepiandrosterone sulphate levels	1.06(0.0118,2.1)	0.641(0.129,1.15)	−0.304(-0.528,-0.0811)	−0.195(-0.496, 0.046)	18.3

Total effect indicates the effect of PM2.5 on Alzheimer’s disease, the direct effect A indicates the effect of PM2.5 on dehydroepiandrosterone sulphate level, the direct effect B indicates the effect of dehydroepiandrosterone sulphate level on Alzheimer’s disease. All the effects were derived by inverse variance weighted. Mediation effect was derived by using delta method.

Figure 4. A scatter plot is used to visualise the causal effect association of PM2.5 and dehydroepiandrosterone sulphate level with Alzheimer’s disease: (A)PM 2.5, (B) dehydroepiandrosterone sulphate. The x-axis showed the SNP effect and SE on each PM2.5 anddehydroepiandrosterone sulphate. The y-axis showed the SNP effect and SE on Alzheimer’s disease.

PM: particulate matter; SNP: single nucleotide polymorphism; SE: standard error.

Figure 5. Leave-one-out sensitivity analysis for the effect of PM2.5 and dehydroepiandrosterone sulphate on Alzheimer’s disease: (A)PM 2.5, (B) dehydroepiandrosterone sulphate. The x-axis showed MR leave-one-out sensitivity analysis for PM2.5 or dehydroepiandrosterone sulphate on Alzheimer’s disease. The y-axis showed the analysis for the effect of leave-one-out of SNPs on Alzheimer’s disease.

MR: Mendelian randomisation; PM: particulate matter; SNP: single nucleotide polymorphism.

Availability of data and materials

The GWAS dataset were publicly available from the IEU open GWAS database (https://gwas.mrcieu.ac.uk/). The functions used in the TwoSampleMR package are available from the website https://mrcieu.github.io/TwoSampleMR/.