Exploring the Causal Relationships and Mediating Factors Between Mental Disorders and Hypertension: A Multivariable Mendelian Randomization Study

Kunyan Li; Chun Yin; Hao Yang; Zhichun Gao; Wang Dong; Jun Jin

doi:10.5334/gh.1483

Figures & Tables

Overview of the study design. Step 1: we used UVMR and MVMR to evaluate the causal relationships between depression, anxiety, panic, and hypertension. Step 2: we screened candidate mediators in the causal association between depression and hypertension, and then we calculated their mediating effects using MVMR. T2DM, type 2 diabetes mellitus; BMI, body mass index; TG, triglycerides; BUN, blood urea nitrogen; HDL, high density lipoprotein.

Table 1

Summary of GWAS data used in the MR analyses.

PHENOTYPE	NO. OF PARTICIPANTS	nSNPs	UNIT	ANCESTRY	CONSORTIUM/COHORT	AUTHOR	YEAR OF PUBLICATION	PMID
Depression	322580	7624934	logOR	European	–	Howard DM	2018	29662059
Anxiety	463010	9851867	SD	European	MRC–IEU	Ben Elsworth	2018	–
Panic	117722	12509516	–	European	–	Neale lab	2018	–
Hypertension	463010	9851867	SD	European	MRC–IEU	Ben Elsworth	2018	–
T2DM	69033	2905211	logOR	European	–	Morris AP	2012	22885922
Smoking	142387	9851867	SD	European	MRC–IEU	Ben Elsworth	2018	–
BMI	99998	7191606	–	European	Within family GWAS consortium	Howe LJ	2022	–
TG	441016	12321875	–	European	UK Biobank	Richardson Tom	2020	32203549
BUN	62403	–	–	European	–	Dennis JK	2021	33441150
HDL	88329	–	–	European	–	Davyson E	2023	36764567
Renal failure	463010	9851867	SD	European	MRC–IEU	Ben Elsworth	2018	–

[i] T2DM: type 2 diabetes mellitus, BMI: body mass index, TG: triglycerides, BUN: blood urea nitrogen, HDL: high density lipoprotein.

Table 2

MVMR estimating the associations of depression, panic, and anxiety with hypertension.

METHOD	EXPOSURE	β (95%CI)	OR (95%CI)	P VALUE	NO OF SNPs	MVMR HETEROGENEITY TEST (IVW/EGGER)		MVMR DIRECTIONAL PLEIOTROPY TEST
METHOD	EXPOSURE	β (95%CI)	OR (95%CI)	P VALUE	NO OF SNPs	Q	P	EGGER INTERCEPT	SE	P
Hypertension
Models with mutual adjustment for depression, anxiety and panic
MV-IVM	depression	0.116 [0.03, 0.202]	1.123 [1.030, 1.224]	0.008	46	71.5173	0.0041
	anxiety	0.463 [–0.377, 1.304]	1.589 [0.686, 3.684]	0.280
	panic	0.073 [–0.013, 0.159]	1.076 [0.987, 1.172]	0.096
MV-Egger	depression	0.164 [0.052, 0.275]	1.178 [1.053, 1.317]	0.004		68.7607	0.0057	0	0	0.194
	anxiety	0.596 [–0.262, 1.454]	1.815 [0.770, 4.280]	0.173
	panic	0.079 [–0.007, 0.165]	1.082 [0.993, 1.179]	0.070
MV-LASSO	depression	0.146 [0.067, 0.225]	1.157 [1.069, 1.252]	<0.001
	anxiety	0.543 [–0.19, 1.276]	1.721 [0.827, 3.582]	0.147
	panic	0.102 [0.024, 0.179]	1.107 [1.024, 1.196]	0.010
MV-median	depression	0.128 [0.026, 0.23]	1.137 [1.026, 1.259]	0.014
	anxiety	0.317 [–0.649, 1.284]	1.373 [0.523, 3.611]	0.520
	panic	0.084 [–0.023, 0.19]	1.088 [0.977, 1.209]	0.124
Models with mutual adjustment for depression and anxiety
MV-IVM	depression	0.148 [0.08, 0.215]	1.160 [1.083, 1.240]	<0.001	27	32.4864	0.1444
MV-IVM	anxiety	0.748 [0.046, 1.45]	2.113 [1.047, 4.263]	0.037
MV-Egger	depression	0.178 [0.075, 0.282]	1.195 [1.078, 1.326]	0.001		31.6913	0.1348	0	0	0.438
MV-Egger	anxiety	0.858 [0.098, 1.618]	2.358 [1.103, 5.043]	0.027
MV-LASSO	depression	0.148 [0.08, 0.215]	1.160 [1.083, 1.240]	<0.001
MV-LASSO	anxiety	0.748 [0.046, 1.45]	2.113 [1.047, 4.263]	0.037
MV-median	depression	0.165 [0.073, 0.257]	1.179 [1.076, 1.293]	<0.001
MV-median	anxiety	0.414 [–0.496, 1.324]	1.513 [0.609, 3.758]	0.373
Models with mutual adjustment for depression and panic
MV-IVM	depression	0.1 [0.042, 0.159]	1.105 [1.043, 1.172]	0.004	93	125.3549	9.90E-03
MV-IVM	panic	0.041 [–0.005, 0.086]	1.042 [0.995, 1.090]	0.078
MV-Egger	depression	0.113 [0.036, 0.19]	1.120 [1.037, 1.209]	0.004		125.0206	8.60E-03	0	0	0.624
MV-Egger	panic	0.043 [–0.003, 0.089]	1.044 [0.997, 1.093]	0.07
MV-LASSO	depression	0.097 [0.041, 0.153]	1.102 [1.042, 1.165]	0.001
MV-LASSO	panic	0.04 [0.000, 0.081]	1.041 [1.000, 1.084]	0.053
MV-median	depression	0.079 [0.004, 0.155]	1.082 [1.004, 1.168]	0.04
MV-median	panic	0.05 [–0.014, 0.113]	1.051 [0.986, 1.120]	0.123
Models with mutual adjustment for anxiety and panic
MV-IVM	anxiety	0.705 [–0.115, 1.526]	2.024 [0.891, 4.600]	0.092	42	67.5684	0.0041
MV-IVM	panic	0.087 [0.009, 0.166]	1.091 [1.009, 1.181]	0.029
MV-Egger	anxiety	0.563 [–0.73, 1.856]	1.756 [0.482, 6.389]	0.394		67.4307	0.0031	0	0	0.778
MV-Egger	panic	0.085 [0.004, 0.166]	1.089 [1.004, 1.181]	0.04
MV-LASSO	anxiety	0.463 [–0.207, 1.134]	1.589 [0.813, 3.108]	0.175
MV-LASSO	panic	0.113 [0.047, 0.180]	1.120 [1.048, 1.197]	0.001
MV-median	anxiety	0.349 [–0.609, 1.306]	1.418 [0.544, 3.691]	0.476
MV-median	panic	0.056 [–0.04, 0.152]	1.058 [0.961, 1.164]	0.252

UVMR and MVMR estimates of the causal associations of depression, anxiety, and panic with hypertension.

Table 3

MVMR estimating the associations of each mediator with hypertension with adjustment for depression.

METHOD	EXPOSURE	β (95%CI)	OR (95%CI)	SE	P	NO OF SNPs	MVMR HETEROGENEITY TEST (IVW/EGGER)		MVMR DIRECTIONAL PLEIOTROPY TEST
METHOD	EXPOSURE	β (95%CI)	OR (95%CI)	SE	P	NO OF SNPs	Q	P	EGGER INTERCEPT	SE	P
T2DM
MV-IVM	depression	0.122[0.017, 0.227]	1.130[1.017, 1.255]	0.054	0.023	37	116.3391	<0.0001
MV-IVM	T2DM	0.01[0.005, 0.015]	1.010[1.005, 1.015]	0.003	<0.001
MV-Egger	depression	0.126[–0.016, 0.269]	1.134[0.984, 1.309]	0.073	0.083		116.3096	<0.0001	0	0	0.926
MV-Egger	T2DM	0.01[0.005, 0.015]	1.010[1.005, 1.015]	0.003	<0.001
MV-LASSO	depression	0.097[0.010, 0.184]	1.102[1.010, 1.202]	0.044	0.029
MV-LASSO	T2DM	0.011[0.007, 0.016]	1.011[1.007, 1.016]	0.002	<0.001
MV-median	depression	0.143[0.033, 0.253]	1.154[1.034, 1.288]	0..56	0.011
MV-median	T2DM	0.012[0.007, 0.018]	1.012[1.007, 1.018]	0.003	<0.001
Smoking
MV-IVM	depression	0.127[0.043, 0.211]	1.135[1.044, 1.235]	0.043	0.003	23	54.0476	0.0001
MV-IVM	smoking	0.036[0.015, 0.058]	1.037[1.015, 1.060]	0.011	0.001
MV-Egger	depression	0.188[0.036, 0.34]	1.207[1.037, 1.405]	0.078	0.015		51.7048	0.0001	0	0	0.341
MV-Egger	smoking	0.04[0.017, 0.063]	1.041[1.017, 1.065]	0.012	0.001
MV-LASSO	depression	0.148[0.088, 0.208]	1.160[1.092, 1.231]	0.031	<0.001
MV-LASSO	smoking	0.032[0.010, 0.054]	1.033[1.010, 1.055]	0.011	0.004
MV-median	depression	0.148[0.064, 0.231]	1.160[1.066, 1.260]	0.043	0.001
MV-median	smoking	0.044[0.016, 0.073]	1.045[1.016, 1.076]	0.014	0.002

Mendelian randomization estimates of mediated effect and proportions mediated by mediators in the causal association between depression and hypertension. T2DM: type 2 diabetes mellitus.

Abbreviation	Term
95%CI	95% confidence intervals
BMI	Body mass index
BUN	Blood urea nitrogen
HDL	High density lipoprotein
IVs	Instrumental variables
IVW	Inverse variance weighting
GWAS	Genome-wide association studies
MR	Mendelian randomization
MVMR	Multivariable Mendelian randomization
OR	Odds ratios
SNPs	Single nucleotide polymorphisms
T2DM	Type 2 diabetes mellitus
TG	Triglycerides
UVMR	Univariate Mendelian randomization

Exploring the Causal Relationships and Mediating Factors Between Mental Disorders and Hypertension: A Multivariable Mendelian Randomization Study

Figures & Tables

Figure 1

Table 1

Table 2

Figure 2

Table 3

Figure 3

Paradigm

My account