Table 5.

Colorectal cancer risk associations identified by methylome-wide association study.

#	CpG	Annotated Gene	Chr	Probe location (bp, GRCh37)	Probe annotation	P S-MultiXcan	Mean z score	Effect size	n models	n indep	Top GWAS SNP at <1Mb	SNP location	P GWAS
1	cg01716680	GJA4	1	35,259,750	S Shore	3.41E-07	−5.099	−0.164	1	1	rs57975061	34,890,238	2.42E-06
2	cg15917621	NRBP1	2	27,650,478	N Shore	1.61E-07	−3.301	−0.094	2	2	rs4665972	27,598,097	1.58E-07
3	cg02609692	LMX1B	9	129,389,125	Island	4.24E-07	5.058	0.112	1	1	rs4075850	130,169,301	1.76E-06
4*	cg12931523	TTLL13	15	90,793,004	S Shore	7.74E-09	4.511	0.067	3	3	rs71407320	91,185,291	3.61E-08
	cg05239308	TTLL13	15	90,793,057	S Shore	1.54E-07	5.364	0.114	3	2	rs71407320	91,185,291	3.61E-08
	cg27018984	TTLL13	15	90,796,558	S Shelf	3.64E-09	−5.900	−0.089	1	1	rs71407320	91,185,291	3.61E-08
5	cg02086790	AXIN1	16	375,327	Island	2.75E-07	2.471	0.042	3	3	rs9921222	375,782	7.10E-07
6*	cg09894072	PLA2G15	16	68,279,487	Island	2.26E-07	5.176	0.096	1	1	rs9939049	68,812,301	1.95E-12
7	cg15135657	LOC100631378	19	38,346,511	S Shore	1.55E-07	−2.170	−0.032	2	2	rs55876653	39,146,780	2.10E-06

SMultiXcan uses a two-sided F-test to quantify the significance of the joint fit of the linear regression of the phenotype on predicted expression from multiple tissue models jointly. All associations shown were methylome-wide significant after Bonferroni correction for 88,888 CpGs with an S-PrediXcan model (P = 0.05/88,888 = 5.62 × 10⁻⁷ for the P_S-MultiXcan). Pairs of CpGs or strings of adjacent CpGs within 1Mb of one another were considered to lie within the same cluster. Five CRC associations were found for which all CpGs were > 1 Mb away from GWAS-significant SNP (P_GWAS < 5 × 10⁻⁸), although near a SNP close to genome-wide significance. Two further associations for 4 CpGs (*) were identified based on conditional MWAS analysis (Supplementary Table 15). Novel CpG hits were all independent of each other and of GWAS SNPs and TWAS genes. Other annotations are as per Table 2.