Table 2

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

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
LocusChrPositionLead variantLead variant locationClosest geneCandidate genes at risk locus:
lead candidate gene(s)
Loci overlapP GWASRARAF
rsIDRAr2 P repl.OR (95% CI)OR dir.I2 P repl.
a) Newly discovered, replicated diverticular disease risk loci
 271576826003rs2056544Intronic SCAPER LD, eQTL: SCAPER , LOC101929439 (RP11-593F23.1), LD: EFTA, C15orf27, ISL2*, RP11-593F23.1*, RCN2* Mag.#47 9.8×10−11 G41.2|42.3rs12443137*G1 0.039 0.93 (0.86 to 1.00)Same43 0.006
 291820028737rs9960286Intergenic CTAGE1 CTAGE1** Mag.#44 2.3×10−10 G25.4|24.4rs2009593*G0.97 0.002 1.14 (1.05 to 1.24)Same0 0.001
 372240695172rs6001870Intronic TNRC6B LD: TNRC6B Mag.#82 4.3×10−9 C36.1|35.1rs5995842*#G0.98 0.025 1.09 (1.01 to 1.18)Same2 0.039
 40415386383rs4132788Intronic C1QTNF7 LD, eQTL: C1QTNF7 1, LD: RP11-665G4.1 Mag.#53 1.1×10−8 T27.0|26.0rs4515160*#G1 0.019 1.10 (1.02 to 1.20)Same35 0.046
 491568238462rs387505Intergenic PIAS1 LD, eQTL: PIAS1 1 **, LD: AC009292.2**, SKOR1** Mag.#54 2.9×10−8 T44.9|43.8rs387505#T1 0.009 1.10 (1.02 to 1.18)Same0 0.017
b) Newly discovered, replicated diverticular disease risk loci—replicated in a meta-analysis with data from MGI
 415122329729rs34126945Intronic SNX24 LD: SNX24, PPIC, SNX2, AC008669.1* Mag.#41 1.2×10−8 G32.3|33.5rs34126945G10.0790.93 (0.86 to 1.01)Same47 0.004
c) Newly discovered diverticular disease risk loci—currently not replicated
 351776856966rs1973232Intronic TIMP2 LD: TIMP2 Mag.#48 2.9×10−9 G19.3|18.5rs9909232A0.920.7641.01 (0.92 to 1.11)Same00.401
 382037493576rs208814Intronic PPP1R16B LD: PPP1R16B
Mag.#75 9.0×10-−9 A36.6|35.5rs208814#A10.6371.02 (0.94 to 1.10)Same00.461
 42632609965rs7990Exon HLA-DQA1 LD: HLA-DQA1, BTNL2*, HLA-DRB9*, BTNL2* eQTL: HLA-DQA2, HLA-DRB1, HLA-DOB, BAG6; N/A1.4×10−8 A10.5|9.9rs2395163*#C0.250.7391.02 (0.92 to 1.12)Same59N/A
 4310124168942rs139760870Intronic PLEKHA1 LD: PLEKHA1, HTRA1*, BTBD16* Mag.#52 1.4×10−8 A5.4|5.9rs117811194*A10.3180.91 (0.76 to 1.09)Same00.181
 47233361425rs6714546Intronic LTBP1 LD, eQTL: LTBP1 1 Mag.#52 2.4×10−8 A30.1|29.1rs6714546#A10.5521.03 (0.94 to 1.11)Same0N/A
 481333727605rs1473813Intronic STARD13 LD: STARD13 Mag.#64 2.9×10−8 A38.0|39.2rs1473813#A10.5070.98 (0.90 to 1.05)Same340.276
d) Novel replicated, previously discovered (Maguire et al) diverticular disease risk loci
 71938738130rs4802297Intergenic PPP1R14A LD, eQTL: PPP1R14A, C19orf33, LD: SPINT2 Mag.#6 2.0×10−16 G49.8|48.2rs12976534*#G1 0.029 1.08 (1.01 to 1.17)Same15 0.004
 97102474903rs72221075Intronic FBXL13 LD: FBXL13,  FAM185A, LRRC17 Mag.#8 7.7×10−15 (-)35.2|33.6rs10257317*#C0.93 3.9×10-4 1.14 (1.06 to 1.23)Same0 9.23×10-4
 1013107897823rs9520339Intronic FAM155A_1 LD: FAM155A Mag.#10 1.1×10−14 T22.7|24.0rs9520344*#A1 0.018 0.90 (0.83 to 0.98)Same0 0.010
 148120456193rs60869342Intergenic NOV LD, eQTL: NOV ,  LD: ENPP2* Mag.#21 4.4×10−13 T23.0|24.2rs1381335*#T0.61 3.0×10-4 0.85 (0.78 to 0.93)Same21 0.001
 152147399453rs111316530Intergenic COL6A1 LD: COL6A1 ,  COL6A2*, AL592528.1, PCBP3*, AL133493.2*, FTCD* Mag.#14 4.8×10−13 (−)15.5|14.5rs7281388*A0.96 0.009 1.16 (1.04 to 1.30)Same0 0.031
 171686233413rs2280028Intergenic LINC01082 LD: LINC01082 Mag.#15 4.1×10−12 A13.2|14.2rs2280028A1 0.019 0.88 (0.79 to 0.98)Same0 0.004
 19698364895rs9482094Intronic LOC101927314 LD: LOC101927314  (RP11-436D23.1) Mag.#19 1.6×10−11 A35.9|37.2rs4839715*#A1 0.022 0.91 (0.85 to 0.99)Same0 0.010
 203151074941rs3732760Intronic P2RY12 LD: P2RY12 ,  P2RY14, MED12L, GPR87, P2RY13* Mag.#16 1.7×10−11 C38.7|37.3rs3732760C1 0.026 1.09 (1.01 to 1.18)Same0 0.049
 221115065235rs575909118Intergenic CALCB LD: CALCB , CALCA Mag.#25 2.8×10−11 T28.6|27.5rs12293178*A0.95 0.020 1.10 (1.02 to 1.19)Same27 0.022
 231151970629rs61814883Intergenic S100A10 LD, eQTL: S100A10 , THEM4 Mag.#22 3.2×10−11 A28.6|29.9rs61814883A1 0.003 0.89 (0.82 to 0.96)Same0 0.030
 251540649609rs71472433Intergenic DISP2 LD, eQTL: PHGR1 1 , DISP2 Mag.#17 6.1×10−11 C17.6|16.6rs71472433C1 0.014 1.14 (1.03 to 1.27)Same0 0.038
 311018440444rs1888693Intronic CACNB2 LD: CACNB2 Mag.#29 2.7×10−10 A33.2|34.3rs1888693A1 0.003 0.89 (0.82 to 0.96)Same0 0.006
 451221066373rs2784255Intergenic HLX LD: HLX , HLX-AS1*, eQTL: LINC01352 (RP11-295M18.2) Mag.#34 2.0×10−8 C47.3|48.5rs2784255C1 0.023 0.92 (0.85 to 0.99)Same0 0.041
 4635843836rs7624168Intergenic EDEM1 neighbouring genes: EDEM1** , GRM7, GRM7-AS3 Mag.#39 2.3×10−8 A21.5|22.6rs4684509*G1 0.036 0.91 (0.83 to 0.99)Same80.389
e) Novel replicated, previously discovered (Maguire et al) diverticular disease risk loci—replicated in a meta-analysis with data from MGI
 5256093204rs18025753′UTR EFEMP1 LD: EFEMP1 , eQTL: RPS27A Mag.#5 3.7×10−19 C14.5|13.3rs1802575C10.1111.10 (0.98 to 1.25)Same47 0.030
 121219294570rs61823192Intronic LYPLAL1-AS1 LD: LYPLAL1-AS1 (RP11-135J2.4), LYPLAL1 Mag.#9 4.6×10−14 T2.5|3.0rs61823192#T10.0820.80 (0.62 to 1.03)Same63 0.003
 1310101391169rs7098322Intergenic SLC25A28 LD: SLC25A28 , COX15, ENTPD7, CUTC Mag.#11 6.0×10−14 C13.4|12.5rs7091203*A10.0761.11 (0.99 to 1.25)Same33 0.043
 21564295363rs10471645Intronic CWC27 LD: CWC27 Mag.#28 2.1×10−11 T17.5|16.5rs2968205*A10.5791.03 (0.93 to 1.14)Same0 0.046
 301742312778rs8074740Intergenic SLC4A1 LD: UBTF , ASB16, C17orf53, TMUB2, ATXN7L3, SLC4A1, AC003102.1, HDAC5; eQTL: ASB16-AS1 Mag.#23 2.4×10−10 A33.4|32.1rs4793086*C0.980.0771.07 (0.99 to 1.16)Same38 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.