Modifiable factors mediating the effects of educational attainment on gestational diabetes mellitus: A two-step Mendelian randomization study

Table 1 Summary of the genome-wide association study data used in the mendelian randomization analyses

Phenotype	Datatype	Sample size	Population	Consortium/cohort
Exposure
Education	Continuous	766345	European	SSGAC
Outcome
GDM	Binary	190879	European	FinnGen
Metabolic factors
BMI1	Continuous	681275	European	GIANT
BF%	Continuous	65831	European	Meta
Waist circumference	Continuous	231353	European	GIANT
WHR1	Continuous	212244	European	GIANT
Total GWG	Continuous	10555	European	EGG
Early GWG	Continuous	7704	European	EGG
Late GWG	Continuous	7681	European	EGG
Hypertension	Binary	342439	European	FinnGen
Systolic blood pressure	Continuous	757601	European	UK Biobank
Diastolic blood pressure	Continuous	757601	European	UK Biobank
LDL-C	Continuous	440546	European	UK Biobank
HDL-Ca	Continuous	403943	European	UK Biobank
Triglyceride	Continuous	441016	European	UK Biobank
Apolipoprotein A-11	Continuous	393193	European	UK Biobank
Apolipoprotein B	Continuous	439214	European	UK Biobank
Serum urate	Continuous	110347	European	GUGC
Serum iron	Continuous	23986	European	GISC
Ferritin	Continuous	23986	European	GISC
Transferrin	Continuous	23986	European	GISC
Transferrin saturation	Continuous	23986	European	GISC
Lifestyle factors
Strenuous sports or other exercises	Continuous	350492	European	UK Biobank
Moderate to vigorous physical activity	Continuous	377234	European	UK Biobank
Sedentary behavior	Continuous	91105	European	UK Biobank
Smoking initiation	Binary	1232091	European	GSCAN
Smoking cessation	Binary	547219	European	GSCAN
Smoking heaviness	Continuous	337334	European	GSCAN
Alcohol drinking	Continuous	941280	European	GSCAN
Coffee consumption	Continuous	375833	European	UK Biobank
Insomnia	Binary	1331010	European	UK Biobank
Sleep duration	Continuous	446118	European	UK Biobank
Long sleep duration	Binary	339926	European	UK Biobank
Short sleep duration	Binary	446118	European	UK Biobank

¹Candidate mediators met all criteria of mediator selection.

GDM: Gestational diabetes mellitus; BMI: Body mass index; BF: Body fat; WHR: Waist-to-hip ratio; GWG: Gestational weight gain; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; SSGAC: Social Science Genetic Association Consortium; GIANT: Genetic Investigation of Anthropometric Traits; EGG: Early Growth Genetics Consortium; GUGC: Global Urate Genetics Consortium; GISC: Genetics of Iron Status Consortium; GSCAN: GWAS & Sequencing Consortium of Alcohol and Nicotine use.

Table 2 Univariable mendelian randomization estimating the causal effect of education on candidate mediators and gestational diabetes mellitus

Phenotype	Method	nSNPs	F-statistics	Beta	95%CI	P value
Outcome
GDM	IVW	294	49.21	-0.34	-0.51 to -0.18	3.80E-05
	MR Egger	294		-0.41	-1.04 to 0.22	0.21
	Weighted Median	294		-0.38	-0.59 to -0.16	5.47E-04
	MR-PRESSO	294		-0.34	-0.51 to -0.18	4.95E-05
Mediators
WHR	IVW	145	47.46	-0.22	-0.29 to -0.16	2.76E-12
	MR Egger	145		-0.36	-0.63 to -0.08	0.01
	Weighted Median	145		-0.23	-0.32 to -0.15	1.16E-07
	MR-PRESSO	145		-0.22	-0.29 to -0.16	9.50E-11
BMI	IVW	106	44.47	-0.16	-0.21 to -0.11	1.97E-10
	MR Egger	106		-0.17	-0.43 to 0.09	0.19
	Weighted Median	106		-0.15	-0.19 to -0.10	7.27E-09
	MR-PRESSO	106		-0.16	-0.21 to -0.11	5.26E-09
HDL-C	IVW	245	46.18	0.18	0.15 to 0.21	1.75E-34
	MR Egger	245		0.15	0.03 to 0.27	0.02
	Weighted Median	245		0.17	0.13 to 0.21	2.81E-20
	MR-PRESSO	245		0.18	0.15 to 0.21	3.38E-27
Apolipoprotein A-1	IVW	266	48.41	0.13	0.10 to 0.16	8.03E-19
	MR Egger	266		0.05	-0.06 to 0.17	0.34
	Weighted Median	266		0.11	0.08 to 0.15	3.07E-10
	MR-PRESSO	266		0.13	0.10 to 0.16	1.19E-16

nSNPs: Number of single-nucleotide polymorphisms; GDM: Gestational diabetes mellitus; WHR: Waist-to-hip ratio; BMI: Body mass index; HDL-C: High density lipoprotein cholesterol; IVW: Inverse variance weighted; MR-PRESSO: Mendelian randomization-pleiotropic residual sum and outliers.

Table 3 Multivariable mendelian randomization assessing the causal association between each mediator and gestational diabetes mellitus with adjustment for education from inverse variance weighted results

Mediators	nSNPs	Beta	SE	OR	95%CI	P value
WHR	154	0.84	0.17	2.31	1.65 to 3.23	1.00E-06
BMI	420	0.42	0.07	1.53	1.32 to 1.76	5.59E-09
HDL-C	381	-0.28	0.04	0.76	0.70 to 0.82	1.59E-10
Apolipoprotein A-1	358	-0.21	0.05	0.81	0.74 to 0.89	6.08E-06

nSNPs: Number of single-nucleotide polymorphisms; WHR: Waist-to-hip ratio; BMI: Body mass index; HDL-C: High density lipoprotein cholesterol.