Causal effect of education on type 2 diabetes: A network Mendelian randomization study

Table 1 Details of studies and datasets used for analyses

Exposure/Outcome	Cases, n	Controls, n	Sample size	PubMed ID	First author	Consortium	Year	Units
Education (discovery data)	NA	NA	293723	27225129	Okbay	SSGAC	2016	SD (yr)
Education 2 (replication data)	NA	NA	226899	UKB-a:505	Neale	Neale Lab	2017	NA
T2DM	34840	114981	77312	22885922	Morris	DIAGRAM plus Metabochip	2012	Log odds
CHD	60801	123504	184305	26343387	Nikpay	CARDIoGRAM plus C4D	2015	Log odds
TG	NA	NA	108514	24097068	Willer	GLGC	2013	SD (mg/dL)
LDL	NA	NA	99073	24097068	Willer	GLGC	2013	SD (mg/dL)
TC	NA	NA	108363	24097068	Willer	GLGC	2013	SD (mg/dL)
BMI	NA	NA	152893	25673413	Locke	GIANT	2015	SD (kg/m2)
WC	NA	NA	232101	25673412	Shungin	GIANT	2015	SD (cm)
WHR	NA	NA	60586	23754948	Randall	GIANT	2013	SD (ratio)
Fasting insulin	NA	NA	38238	20081858	Dupuis	MAGIC	2010	Log pmol/L
Fasting glucose	NA	NA	58074	22581228	Manning	MAGIC	2012	mmol/L
HbA1c	NA	NA	46368	20858683	Soranzo	MAGIC	2010	%

BMI: Body mass index; CHD: Coronary heart disease; GIANT: Genetic Investigation of Anthropometric Traits; HbA1c: Glycated hemoglobin; LDL: Low-density lipoprotein; MAGIC: Mapping and Geographic Information Consortium; NA: Not available; SSGAC: Social Science Genetic Association Consortium; TC: Total cholesterol; T2DM: Type 2 diabetes mellitus; TG: Triglycerides; WC: Waist circumference; WHR: Waist-to-hip ratio.

Table 2 Causal associations between genetically determined education and type 2 diabetes mellitus

Trait	Method	nSNP	OR	95%CI		P value	Heterogeneity P	MR Egger intercept P
Education-T2DM	MR Egger	17	0.381	0.047	3.093	0.381	0.124	0.979
	Weighted median	17	0.406	0.246	0.672	0.000
	Inverse variance weighted	17	0.392	0.263	0.583	0.000	0.163

MR: Mendelian randomization; OR: Odds ratio; nSNP: Number of single-nucleotide polymorphisms; T2DM: Type 2 diabetes mellitus.

Table 3 Causal association between genetically determined education and metabolic risk factors

Trait	Method	nSNP	Beta	SE	P value	Heterogeneity P	MR Egger intercept P
Discovery (education-metabolic risk factors)
CHD	MR Egger	71	0.145	0.417	0.729	0.123	0.263
	Weighted median	71	-0.238	0.107	0.026
	Inverse variance weighted	71	-0.318	0.079	0.000	0.117
TG	MR Egger	57	-0.183	0.263	0.489	0.112	0.937
	Weighted median	57	-0.192	0.057	0.001
	Inverse variance weighted	57	-0.204	0.043	0.000	0.130
LDL	MR Egger	57	-0.274	0.275	0.324	0.316	0.415
	Weighted median	57	0.007	0.063	0.909
	Inverse variance weighted	57	-0.051	0.045	0.261	0.326
TC	MR Egger	57	-0.087	0.277	0.755	0.197	0.838
	Weighted median	57	-0.018	0.064	0.775
	Inverse variance weighted	57	-0.031	0.045	0.500	0.223
BMI	MR Egger	59	0.013	0.353	0.970	0.000	0.415
	Weighted median	59	-0.209	0.048	0.000
	Inverse variance weighted	59	-0.272	0.058	0.000	0.000
WC	MR Egger	59	-0.002	0.404	0.996	0.000	0.429
	Weighted median	59	-0.269	0.056	0.000
	Inverse variance weighted	59	-0.319	0.066	0.000	0.000
WHR	MR Egger	58	-0.743	0.461	0.113	0.028	0.346
	Weighted median	58	-0.298	0.097	0.002
	Inverse variance weighted	58	-0.311	0.076	0.000	0.027
Fasting insulin	MR Egger	58	-0.269	0.215	0.215	0.010	0.312
	Weighted median	58	-0.039	0.048	0.419
	Inverse variance weighted	58	-0.053	0.035	0.129	0.014
Fasting glucose	MR Egger	58	-0.185	0.172	0.287	0.167	0.398
	Weighted median	58	-0.044	0.039	0.257
	Inverse variance weighted	58	-0.041	0.028	0.152	0.172
HbA1c	MR Egger	58	0.004077	0.1779	0.9818	0.5674	0.889
	Weighted median	58	-0.009323	0.04094	0.8199
	Inverse variance weighted	58	-0.02056	0.02908	0.4796	0.6038
Replication (education-metabolic risk factors)
CHD	MR Egger	20	-0.985	0.772	0.218	0.196	0.537
	Weighted median	20	-0.474	0.209	0.024
	Inverse variance weighted	20	-0.511	0.164	0.002	0.222
TG	MR Egger	13	0.099	1.076	0.928	0.000	0.702
	Weighted median	13	-0.161	0.134	0.229
	Inverse variance weighted	13	-0.319	0.163	0.051	0.000
BMI	MR Egger	14	0.830	0.582	0.179	0.079	0.071
	Weighted median	14	-0.381	0.106	0.000
	Inverse variance weighted	14	-0.308	0.095	0.001	0.018
WC	MR Egger	14	0.669	0.637	0.314	0.179	0.169
	Weighted median	14	-0.246	0.113	0.030
	Inverse variance weighted	14	-0.252	0.096	0.009	0.118
WHR	MR Egger	15	0.235	1.375	0.867	0.010	0.661
	Weighted median	15	-0.511	0.222	0.021
	Inverse variance weighted	15	-0.375	0.213	0.079	0.014

BMI: Body mass index; CHD: Coronary heart disease; HbA1c: Glycated hemoglobin; LDL: Low-density lipoprotein; MR: Mendelian randomization; nSNP: Number of Single-nucleotide polymorphisms; TC: Total cholesterol; T2DM: Type 2 diabetes mellitus; TG: Triglycerides; WC: Waist circumference; WHR: Waist-to-hip ratio.

Table 4 Causal association between genetically determined metabolic risk factors and type 2 diabetes mellitus

Trait	Method	nSNP	OR	95%CI		P value	Heterogeneity P	MR Egger intercept P
CHD-T2DM	MR Egger	28	0.947	0.697	1.288	0.733	0.000	0.815
	Weighted median	28	1.111	0.996	1.239	0.059
	Inverse variance weighted	28	1.073	0.954	1.207	0.243	0.000
BMI-T2DM	MR Egger	72	3.370	1.328	8.556	0.013	0.000	0.240
	Weighted median	72	2.622	2.164	3.178	0.000
	Inverse variance weighted	72	2.046	1.374	3.048	0.000	0.000
WC-T2DM	MR Egger	39	11.670	1.590	85.654	0.021	0.000	0.049
	Weighted median	39	2.371	1.788	3.145	0.000
	Inverse variance weighted	39	1.607	0.879	2.938	0.123	0.000

BMI: Body mass index; CHD: Coronary heart disease; MR: Mendelian randomization; OR: Odds ratio; nSNP: Number of single-nucleotide polymorphisms; T2DM: Type 2 diabetes mellitus; WC: Waist circumference.