Table 3.

Mendelian randomization analysis results of causal CpG sites for metabolic traits, selected among the top ten EWAS most significant hits

Exposure	MR resultsa					EWAS resultsb				CHR	CpG position in Genome Build 37	Reference genec	Location of CpG related to genec	Relation to CpG Islandd
	Outcome	N SNPs	Beta	SE	p-value	CpG data	Beta	SE	p-value
cg11622362	Glucose	2	0.019	0.005	0.0001	T0	− 1.05	0.22	2.96 × 10–5	11	34,938,112	APIP*	TSS200	Island
cg09137125	Glucose	2	− 0.003	0.007	0.63	T0	− 0.93	0.19	3.51 × 10–5	10	7,486,981
cg26295559	Glucose	4	0.003	0.004	0.55	T0-T1	− 2.40	0.46	1.02 × 10–5	7	158,550,318	ESYT2	Body
cg09694300	HDL	2	− 0.025	0.019	0.18	T0	− 1.25	0.28	5.58 × 10–5	3	159,429,667	SCHIP1	Body
cg23700124	LDL	2	0.001	0.005	0.86	T0	− 0.69	0.14	1.15 × 10–5	4	123,843,736	SPATA5*	TSS1500	Island
cg03803210	TG	3	0.001	0.005	0.87	T0-T1	1.93	0.34	8.93 × 10–7	8	17,438,816	PDGFRL	Body	S_Shelf
cg08387293	TG	2	0.002	0.008	0.82	T0-T1	− 3.22	0.58	1.13 × 10–6	1	984,383	AGRN	Body	Island

CHR chromosome, EWAS epigenome-wide association study, HDL high density lipoprotein cholesterol, LDL low-density lipoprotein cholesterol, MR Mendelian randomization, SE standard error, SNPs single nucleotide polymorphisms, TG triglycerides

^aTwo-sample MR analyses using the inverse-variance weighted method were performed. Summary statistics for instrument-exposure association (n = 3,841) were retrieved from Bonder et al. [40], while instrument-outcome association statistics were derived from GWAS performed in the UKBiobank (http://www.nealelab.is/uk-biobank; n = 314′916 for glucose, n = 315′133 for HDL, n = 343′621 for LDL, n = 343,992 for TG). Significant p-values (< 0.05) are indicated in bold

^bThe results of the EWAS using methylation M-values are displayed. For the first line, the magnitude of the effect in β-value is to be interpreted as follows: a difference of 1.4% in baseline methylation level (corresponding to baseline methylation IQR in PsyMetab sample) is associated with a 0.39 mM (SE = 0.07) smaller glucose increase. No result reached statistical significance

^cReference genes for the methylation sites, and gene regions where the CpGs are located according to the UCSC database. Empty fields indicate an intergenic location

*Specifies there exists > 1 gene or gene transcript at this location. TSS200 = 0–200 bases upstream of the transcriptional start site (TSS); TSS1500 = 200–1500 bases upstream of the TSS; Body = between the ATG and stop codon, irrespective of the presence of introns, exons, TSS, or promoters

^dThe relation to a putative nearby CpG island, according to the UCSC database, is given. S_Shelf = 2–4 kb downstream (3′) of CpG island