Association of education with cholelithiasis and mediating effects of cardiometabolic factors: A Mendelian randomization study

Table 1 Summary of GWAS data in Mendelian randomization analyses

Phenotype	Unit	No. of participants	Ancestry	Consortium/cohort	Ref.	GWAS resources
Education	SD (4.2 years)	1131881	European	SSGAC	Lee et al[32], 2018
Cognition	SD (0.99 point)	257841	European	COGENT	Lee et al[32], 2018
Intelligence	SD	269867	European	Meta	Savage et al[25], 2018
Cholelithiasis	Event	330903	European	FinnGen	Not available	https://r9.finngen.fi/
Cholecystitis	Event	330903	European	FinnGen	Not available	https://r9.finngen.fi/
BMI	SD (4.7 kg/m2)	681275	European	GIANT	Yengo et al[34], 2018
BF%	SD (6.6%)	65831	European	Meta	Lu et al[35], 2016
WHR	SD (0.09)	212244	European	GIANT	Shungin et al[36], 2015
Waist circumference	SD (12.5 cm)	231353	European	GIANT	Shungin et al[36], 2015
Watching TV	SD (1.5 h)	408815	European	United Kingdom Biobank	Van de Vegte et al[44], 2020
Childhood obesity	Event	13848	European	EGG	Bradfield et al[37], 2012
Type 2 diabetes	Event	70127	European	Meta	Sílvia Bonàs-Guarch et al[38], 2018
Fasting insulin	SD (0.79 pmol/L)	108557	European	MAGIC	Scott et al[39], 2012
Fasting glucose	SD (0.73 mmol/L)	133010	European	MAGIC	Scott et al[39], 2012
LDL-C	SD (38.7 mg/dL)	173082	Mixed1	GLGC	Willer et al[40], 2013
HDL-C	SD (15.5 mg/dL)	187167	Mixed1	GLGC	Willer et al[40], 2013
Triglycerides	SD (90.7 mg/dL)	177861	Mixed1	GLGC	Willer et al[40], 2013
Total cholesterol	SD (41.8 mg/dL)	187365	Mixed1	GLGC	Willer et al[40], 2013
Smoking initiation	Event	607291	European	GSCAN	Liu et al[41], 2019
Smoking heaviness	SD (8 cigarettes)	337334	European	GSCAN	Liu et al[41], 2019
Alcohol drinking	SD (9 drinks/wk)	335394	European	GSCAN	Liu et al[41], 2019
Coffee intake	SD (1% change)	375833	European	United Kingdom Biobank	Zhong et al[42], 2019
Tea intake	SD (2.85 cups/d)	447485	European	United Kingdom Biobank	Zhong et al[42], 2019	UKB-b-6066
MVPA	SD (2084 MET-min/wk)	377234	European	United Kingdom Biobank	Klimentidis et al[43], 2018
Computer using	SD (1.2 h)	408815	European	United Kingdom Biobank	Van de Vegte et al[44], 2020
Total house income	SD	397751	European	United Kingdom Biobank	Hemani et al[45], 2018

¹Thirty-seven of forty-five studies for summary statistics consisted preliminarily of participants of European ancestry.

BF%: Body fat percentage; BMI: Body mass index; COGENT: Cognitive Genomics Consortium; EGG: Early Growth Genetics Consortium; GIANT: Genetic Investigation of Anthropometric Traits; GLGC: Global Lipids Genetics Consortium; GSCAN: GWAS & Sequencing Consortium of Alcohol and Nicotine use; GWAS: Genome-wide association study; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; MR: Mendelian randomization; MVMR: Multivariable Mendelian randomization; MVPA: Moderate to vigorous physical activity; PGC: Psychiatric Genomic Consortium; SSGAC: Social Science Genetic Association Consortium; TV: Television; WHR: Waist-to-hip ratio.

Table 2 MVMR estimating causal associations between education, cognition, or intelligence and cholecystitis with adjustment for cholelithiasis

Exposure	Method	β (95%CI)	OR (95%CI)	P value
Education	MR MV_IVW	-0.534 (-0.767 to -0.300)	0.292 (0.171-0.501)	1.73E-43
	MR MV_Egger	-0.614 (-0.853 to -0.376)	0.243 (0.140-0.421)	< 0.001
	MR MV_Median	-0.608 (-0.942 to -0.275)	0.247 (0.114-0.531)	< 0.001
	MR MV_Lasso	-0.513 (-0.738 to -0.288)	0.307 (0.183-0.515)	< 0.001
Cognition	MR MV_IVW	-0.026 (-0.222 to 0.222)	0.942 (0.600-1.667)	0.839
	MR MV_Egger	-0.894 (-1.590 to -0.197)	0.128 (0.026-1.574)	0.012
	MR MV_Median	0.094 (-0.234 to 0.421)	1.242 (0.583-2.636)	0.576
	MR MV_Lasso	-0.025 (-0.247 to 0.196)	0.944 (0.566-1.570)	0.822
Intelligence	MR MV_IVW	-0.079 (-0.296 to 0.138)	0.834 (0.506-1.374)	0.475
	MR MV_Egger	-0.454 (-1.171 to 0.264)	0.352 (0.067-1.837)	0.215
	MR MV_Median	-0.105 (-0.414 to 0.203)	0.785 (0.385-1.596)	0.504
	MR MV_Lasso	-0.122 (-0.328 to 0.084)	0.755 (0.470-1.213)	0.246

MR: Mendelian randomization.

Table 3 UVMR estimating causal associations between education, cognition, and intelligence and each mediator

Exposure	Mediator	Method	No. of SNPs	β (95%CI)	P value
Education	BMI	IVW	332	-0.36 (-0.42 to -0.31)	9.57E-39
		MR Egger	332	-0.30 (-0.50 to -0.10)	2.92E-03
		Weighted Median	332	-0.29 ( -0.33 to -0.25)	1.56E-46
		MR PRESSO	651	-0.35 (-0.37 to -0.33)	1.44E-60
	BF%	IVW	332	-0.28 (-0.32 to -0.24)	1.10E-41
		MR Egger	332	-0.24 (-0.38 to -0.10)	1.11E-03
		Weighted Median	332	-0.24 (-0.28 to -0.21)	7.71E-51
		MR PRESSO	541	-0.29 (-0.30 to -0.28)	5.98E-66
	Waist circumference	IVW	271	-0.30 (-0.36 to -0.23)	5.57E-20
		MR Egger	271	-0.41 (-0.66 to -0.17)	1.11E-03
		Weighted Median	271	-0.26 (-0.34 to -0.18)	1.96E-10
		MR PRESSO	91	-0.27 (-0.30 to -0.24)	3.59E-22
	WHR	IVW	271	-0.28 (-0.34 to -0.23)	5.91E-26
		MR Egger	271	-0.32 (-0.53 to -0.12)	1.89E-03
		Weighted Median	271	-0.25 (-0.32 to -0.17)	2.26E-10
		MR PRESSO	21	-0.28 (-0.31 to -0.25)	1.31E-25
	Watching TV	IVW	332	-0.41 (-0.44 to -0.39)	9.10E-226
		MR Egger	332	-0.44 (-0.53 to -0.35)	9.50E-19
		Weighted Median	332	-0.38 (-0.41 to -0.35)	7.23E-145
		MR PRESSO	121	-0.42 (-0.44 to -0.40)	2.22E-127
Cognition	Watching TV	IVW	106	-0.20 (-0.24 to -0.16)	5.11E-25
		MR Egger	106	-0.26 (-0.42 to -0.10)	1.57E-03
		Weighted Median	106	-0.20 (-0.18 to -0.11)	1.43E-20
		MR PRESSO	171	-0.18 (-0.20 to -0.16)	1.78E-26
Intelligence	Watching TV	IVW	136	-0.21(-0.25 to -0.18)	1.77E-36
		MR Egger	136	-0.32(-0.47 to -0.16)	9.16E-05
		Weighted Median	136	-0.19(-0.22 to -0.16)	3.76E-42
		MR PRESSO	211	-0.20(-0.22 to -0.18)	4.11E-32

¹Number of outliers. BMI: Body mass index; MR: Mendelian randomization; SNPs: Single nucleotide polymorphisms; TV: Television; IVW: Inverse variance weighted; WHR: Waist-to-hip ratio.

Table 4 MVMR estimating causal associations between each mediator and cholelithiasis with adjustment for education, cognition, or intelligence

Exposure	Mediator	β (95%CI)	OR (95%CI)	P value
Education	BMI	0.469 (0.369-0.569)	1.60 (1.45-1.77)	4.97E-20
	BF%	0.665 (0.525-0.805)	1.94 (1.69-2.24)	1.45E-20
	Waist circumference	0.447 (0.282-0.612)	1.56 (1.33-1.84)	1.13E-07
	WHR	0.361 (0.130-0.592)	1.43 (1.14-1.81)	2.19E-03
	Time spent watching TV	0.372 (0.173-0.571)	1.45 (1.06-1.75)	4.29E-02
Cognition	Time spent watching TV	0.357 (0.071-0.643)	1.42 (1.07-1.90)	1.44E-02
Intelligence	Time spent watching TV	0.382 (0.056-0.708)	1.46 (1.05-2.03)	2.17E-02

BMI: Body mass index; TV: Television; WHR: Waist-to-hip ratio.