Table 2

GWAS and replication results: newly discovered and novel replicated risk loci

Discovery											Replication							Replication
GWAS in UK Biobank diverticular disease (DD) 31 917, controls (CON) 419 135											European samples DD 3893, diverticula-free CON 2829							European and MGI samples DD: 4611 CON: 31 478
Locus	Chr	Position	Lead variant	Lead variant location	Closest gene	Candidate genes at risk locus: lead candidate gene(s)	Loci overlap	P GWAS	RA	RAF Ca\|Co	rsID	RA	r²	P repl.	OR (95% CI)	OR dir.	I²	P repl.
a) Newly discovered, replicated diverticular disease risk loci
27	15	76826003	rs2056544	Intronic	*SCAPER*	LD, eQTL: *SCAPER* , LOC101929439 (RP11-593F23.1), LD: EFTA, C15orf27, ISL2, RP11-593F23.1, RCN2*	Mag.#47	9.8×10⁻¹¹	G	41.2\|42.3	rs12443137*	G	1	0.039	0.93 (0.86 to 1.00)	Same	43	0.006
29	18	20028737	rs9960286	Intergenic	*CTAGE1*	CTAGE1**	Mag.#44	2.3×10⁻¹⁰	G	25.4\|24.4	rs2009593*	G	0.97	0.002	1.14 (1.05 to 1.24)	Same	0	0.001
37	22	40695172	rs6001870	Intronic	*TNRC6B*	LD: TNRC6B	Mag.#82	4.3×10⁻⁹	C	36.1\|35.1	rs5995842*#	G	0.98	0.025	1.09 (1.01 to 1.18)	Same	2	0.039
40	4	15386383	rs4132788	Intronic	*C1QTNF7*	LD, eQTL: *C1QTNF7* ¹, LD: RP11-665G4.1	Mag.#53	1.1×10⁻⁸	T	27.0\|26.0	rs4515160*#	G	1	0.019	1.10 (1.02 to 1.20)	Same	35	0.046
49	15	68238462	rs387505	Intergenic	*PIAS1*	LD, eQTL: *PIAS1* ¹ , LD: AC009292.2, SKOR1**	Mag.#54	2.9×10⁻⁸	T	44.9\|43.8	rs387505#	T	1	0.009	1.10 (1.02 to 1.18)	Same	0	0.017
b) Newly discovered, replicated diverticular disease risk loci—replicated in a meta-analysis with data from MGI
41	5	122329729	rs34126945	Intronic	*SNX24*	LD: SNX24, PPIC, SNX2, AC008669.1*	Mag.#41	1.2×10⁻⁸	G	32.3\|33.5	rs34126945	G	1	0.079	0.93 (0.86 to 1.01)	Same	47	0.004
c) Newly discovered diverticular disease risk loci—currently not replicated
35	17	76856966	rs1973232	Intronic	TIMP2	LD: TIMP2	Mag.#48	2.9×10⁻⁹	G	19.3\|18.5	rs9909232	A	0.92	0.764	1.01 (0.92 to 1.11)	Same	0	0.401
38	20	37493576	rs208814	Intronic	PPP1R16B	LD: PPP1R16B eQTL: *FAM83D*	Mag.#75	9.0×10^-−9	A	36.6\|35.5	rs208814#	A	1	0.637	1.02 (0.94 to 1.10)	Same	0	0.461
42	6	32609965	rs7990	Exon	HLA-DQA1	LD: HLA-DQA1, BTNL2, HLA-DRB9, BTNL2* eQTL: HLA-DQA2, HLA-DRB1, HLA-DOB, BAG6;	N/A	1.4×10⁻⁸	A	10.5\|9.9	rs2395163*#	C	0.25	0.739	1.02 (0.92 to 1.12)	Same	59	N/A
43	10	124168942	rs139760870	Intronic	PLEKHA1	LD: PLEKHA1, HTRA1, BTBD16	Mag.#52	1.4×10⁻⁸	A	5.4\|5.9	rs117811194*	A	1	0.318	0.91 (0.76 to 1.09)	Same	0	0.181
47	2	33361425	rs6714546	Intronic	LTBP1	LD, eQTL: *LTBP1* ¹	Mag.#52	2.4×10⁻⁸	A	30.1\|29.1	rs6714546#	A	1	0.552	1.03 (0.94 to 1.11)	Same	0	N/A
48	13	33727605	rs1473813	Intronic	STARD13	LD: STARD13	Mag.#64	2.9×10⁻⁸	A	38.0\|39.2	rs1473813#	A	1	0.507	0.98 (0.90 to 1.05)	Same	34	0.276
d) Novel replicated, previously discovered (Maguire et al) diverticular disease risk loci
7	19	38738130	rs4802297	Intergenic	*PPP1R14A*	LD, eQTL: PPP1R14A, C19orf33, LD: SPINT2	*Mag.#6*	2.0×10⁻¹⁶	G	49.8\|48.2	rs12976534*#	G	1	0.029	1.08 (1.01 to 1.17)	Same	15	0.004
9	7	102474903	rs72221075	Intronic	*FBXL13*	LD: FBXL13, FAM185A, LRRC17	*Mag.#8*	7.7×10⁻¹⁵	(-)	35.2\|33.6	rs10257317*#	C	0.93	3.9×10^-4	1.14 (1.06 to 1.23)	Same	0	9.23×10^-4
10	13	107897823	rs9520339	Intronic	*FAM155A_1*	LD: *FAM155A*	*Mag.#10*	1.1×10⁻¹⁴	T	22.7\|24.0	rs9520344*#	A	1	0.018	0.90 (0.83 to 0.98)	Same	0	0.010
14	8	120456193	rs60869342	Intergenic	*NOV*	LD, eQTL: NOV , LD: ENPP2*	*Mag.#21*	4.4×10⁻¹³	T	23.0\|24.2	rs1381335*#	T	0.61	3.0×10^-4	0.85 (0.78 to 0.93)	Same	21	0.001
15	21	47399453	rs111316530	Intergenic	*COL6A1*	LD: COL6A1 , COL6A2, AL592528.1, PCBP3, AL133493.2, FTCD	*Mag.#14*	4.8×10⁻¹³	(−)	15.5\|14.5	rs7281388*	A	0.96	0.009	1.16 (1.04 to 1.30)	Same	0	0.031
17	16	86233413	rs2280028	Intergenic	*LINC01082*	LD: *LINC01082*	*Mag.#15*	4.1×10⁻¹²	A	13.2\|14.2	rs2280028	A	1	0.019	0.88 (0.79 to 0.98)	Same	0	0.004
19	6	98364895	rs9482094	Intronic	*LOC101927314*	LD: *LOC101927314* (RP11-436D23.1)	*Mag.#19*	1.6×10⁻¹¹	A	35.9\|37.2	rs4839715*#	A	1	0.022	0.91 (0.85 to 0.99)	Same	0	0.010
20	3	151074941	rs3732760	Intronic	*P2RY12*	LD: P2RY12 , P2RY14, MED12L, GPR87, P2RY13*	*Mag.#16*	1.7×10⁻¹¹	C	38.7\|37.3	rs3732760	C	1	0.026	1.09 (1.01 to 1.18)	Same	0	0.049
22	11	15065235	rs575909118	Intergenic	*CALCB*	LD: CALCB , CALCA	*Mag.#25*	2.8×10⁻¹¹	T	28.6\|27.5	rs12293178*	A	0.95	0.020	1.10 (1.02 to 1.19)	Same	27	0.022
23	1	151970629	rs61814883	Intergenic	*S100A10*	LD, eQTL: *S100A10* , THEM4	*Mag.#22*	3.2×10⁻¹¹	A	28.6\|29.9	rs61814883	A	1	0.003	0.89 (0.82 to 0.96)	Same	0	0.030
25	15	40649609	rs71472433	Intergenic	*DISP2*	LD, eQTL: *PHGR1* ¹ *, DISP2*	*Mag.#17*	6.1×10⁻¹¹	C	17.6\|16.6	rs71472433	C	1	0.014	1.14 (1.03 to 1.27)	Same	0	0.038
31	10	18440444	rs1888693	Intronic	*CACNB2*	LD: *CACNB2*	*Mag.#29*	2.7×10⁻¹⁰	A	33.2\|34.3	rs1888693	A	1	0.003	0.89 (0.82 to 0.96)	Same	0	0.006
45	1	221066373	rs2784255	Intergenic	*HLX*	LD: HLX , HLX-AS1, eQTL: LINC01352 (RP11-295M18.2)*	*Mag.#34*	2.0×10⁻⁸	C	47.3\|48.5	rs2784255	C	1	0.023	0.92 (0.85 to 0.99)	Same	0	0.041
46	3	5843836	rs7624168	Intergenic	*EDEM1*	neighbouring genes: EDEM1** , GRM7, GRM7-AS3	*Mag.#39*	2.3×10⁻⁸	A	21.5\|22.6	rs4684509*	G	1	0.036	0.91 (0.83 to 0.99)	Same	8	0.389
e) Novel replicated, previously discovered (Maguire et al) diverticular disease risk loci—replicated in a meta-analysis with data from MGI
5	2	56093204	rs1802575	3′UTR	*EFEMP1*	LD: EFEMP1 , eQTL: RPS27A	*Mag.#5*	3.7×10⁻¹⁹	C	14.5\|13.3	rs1802575	C	1	0.111	1.10 (0.98 to 1.25)	Same	47	0.030
12	1	219294570	rs61823192	Intronic	*LYPLAL1-AS1*	LD: *LYPLAL1-AS1* (RP11-135J2.4), LYPLAL1	*Mag.#9*	4.6×10⁻¹⁴	T	2.5\|3.0	rs61823192#	T	1	0.082	0.80 (0.62 to 1.03)	Same	63	0.003
13	10	101391169	rs7098322	Intergenic	*SLC25A28*	LD: SLC25A28 , COX15, ENTPD7, CUTC	*Mag.#11*	6.0×10⁻¹⁴	C	13.4\|12.5	rs7091203*	A	1	0.076	1.11 (0.99 to 1.25)	Same	33	0.043
21	5	64295363	rs10471645	Intronic	*CWC27*	LD: *CWC27*	*Mag.#28*	2.1×10⁻¹¹	T	17.5\|16.5	rs2968205*	A	1	0.579	1.03 (0.93 to 1.14)	Same	0	0.046
30	17	42312778	rs8074740	Intergenic	*SLC4A1*	LD: UBTF , ASB16, C17orf53, TMUB2, ATXN7L3, SLC4A1, AC003102.1, HDAC5; eQTL: ASB16-AS1	*Mag.#23*	2.4×10⁻¹⁰	A	33.4\|32.1	rs4793086*	C	0.98	0.077	1.07 (0.99 to 1.16)	Same	38	0.019

Results of GWAS analysis in diverticular disease. The column ‘loci overlap’ indicates an overlap of the respective risk loci to a risk locus recently identified in a GWAS by Maguire et al.15 The corresponding risk locus number is given as (Mag.#1–82), with bold print indicating prior attainment of genome-wide significance. Current GWAS risk loci are numbered descending by the p value in the discovery analysis. Ranked discovery GWAS and replication tables are provided in online supplementary table 5 and 6. Results are structured showing: a) newly discovered diverticular disease risk loci with genome-wide significance replicated in European samples with diverticula-free CON (table 1); b) replicated in a meta-analysis of European samples of the current study and Michigan samples with population controls (MGI); c) newly discovered diverticular disease risk loci currently lacking replication and d, e) showing novel replicated, previously discovered (Maguire et al) diverticular disease risk loci replicated c) in European samples and d) replicated in a meta-analysis of European samples of the current study and Michigan samples with population controls (MGI). Bold gene symbols and bold P repl. indicate replication using an false discovery rate (FDR) of 0.1 after Benjamin-Hochberg correction. The lead candidate gene annotation corresponds to the curated candidate gene(s), which is described in online supplementary materials and methods and in supplementary table 3. Candidate genes that harbour variants in LD (r²>0.8) to the respective lead variant at genomic risk locus are indicated with ‘LD’, additional candidate genes with variants with p<1.0 × 10^-5 and r2 >0.6 to independent significant lead variants are marked with an asterisk (*). At intergenic annotated risk loci, if the lead variant or proxy variants are not mapping to a specific gene, closest neighbouring candidate genes (<1 cM distance) are marked with (**). Candidate genes with eQTL variants affecting gene expression in sigmoid colon at FDR<0.05 or at nominal p_eQTL<0.05 are shown (data from GTExV7). Additional candidate genes mapped by three-dimensional chromatin interactions are listed in online supplementary table 2 for each risk locus. rsIDs of replication SNP which are proxies for the discovery variant are marked with an asterisk (*) and pairwise LD (r²) to the discovery variant is provided. SNPs genotyped by TaqMan rather than iPLEX are indicated by a pound (#) sign. Variants at the FAM155A-1 and FAM155A-2 (table 3) were in low LD (r²=0.0043) and thus considered as individual loci. ORs are based on the reference allele (RA). Reference allele frequencies (RAF%) are provide for cases/controls in the discovery GWAS. I² measure of the percentage of between-cohort heterogeneity. The direction of obtained OR (OR dir.) between discovery and replication analysis is consistent for all reported loci. The positions of lead variants were annotated according to Genome Reference Consortium Human Build 37 patch release 13. Gene annotation are based on RefSeq curated gene predictions from NCBI; pseudogenes were excluded from annotation.
GWAS, genome-wide association study; MGI, Michigan genome initiative; N/A, not available; UTR, untranslated region.