Table 1. PBC risk loci identified in the current study.
|
a. Confirmed risk loci (validation
P<4.4 × 10−4
resulting in combined
P<5 × 10−8) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Locus | SNP | Position (build 38) | A1/A2 | DiscoveryP | ValidationP | JointP | OR (95% CI) | Region (build 38) | Nearby genes and functional annotation* | Autoimmune overlap |
| 2q12.1 | rs12712133 | 102,249,813 | A/G | 1.62 × 10−5 | 7.94 × 10−5 | 5.19 × 10−9 | 1.14 (1.07–1.21) | 102,118,975–102,438,307 | IL1R1, IL1RL2†, FAM183DP, IL1RL1‡, IL18R1, LOC100422339, IL18RAP, MIR4772 | CD, CeD |
| 2q36.3 | rs4973341 | 227,795,646 | C/T | 6.48 × 10−7 | 7.73 × 10−5 | 2.34 × 10−10 | 0.82 (0.74–0.90) | 227,747,828–227,815,647 | RNA5SP121, SNRPGP8, LOC100533842, CCL20†,§ | |
| 4p16.3 | rs11724804 | 971,991 | A/G | 3.67 × 10−7 | 4.25 × 10−6 | 9.01 × 10−12 | 1.22 (1.12–1.33) | 853,681–1,014,424 | GAK, TMEM175, DGKQ†, SLC26A1a, IDUA, FGFRL1 | |
| 5q21.1 | rs526231 | 103,345,680 | T/C | 3.10 × 10−5 | 9.39 × 10−5 | 1.14 × 10−8 | 0.87 (0.81–0.93) | 102,939,698–103,416,571 | PAM§, EIF3KP1, GIN1, PPIP5K2, C5orf30‡,§ | RA |
| 5q33.3 | rs2546890 | 159,332,892 | G/A | 1.20 × 10−6 | 1.89 × 10−5 | 1.06 × 10−10 | 0.87 (0.82–0.93) | 159,117,927–159,414,310 | RNF145, UBLCP1, RNU4ATAC2P, IL12B, LOC285626† | Pso, MS, CD |
| 6q23.3 | rs6933404 | 137,638,098 | C/T | 9.47 × 10−7 | 2.84 × 10−5 | 1.27 × 10−10 | 1.18 (1.09–1.27) | 137,571,557–137,803,754 | LOC102723649, LOC442263, OLIG3†, TNFAIP3† | RA, SLE, SjS, CeD, UC, MS |
|
b. Suggestive risk loci (validation
P<1 × 10−3) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Locus | SNP | Position (build 38) | A1/A2 | DiscoveryP | ValidationP | JointP | OR for A1 (95% CI) | Region (build 38) | Nearby genes and functional annotation* | Autoimmune overlap |
| 5q23.1 | rs2434360 | 116,057,393 | T/G | 3.20 × 10−3 | 9.94 × 10−4 | 1.04 × 10−5 | 1.14 (1.05–1.23) | 116,032,882–116,163,459 | RPS25P6, ARL14EPL, COMMD10 | |
| 16p11 | rs1859308 | 27,386,677 | T/C | 7.72 × 10−5 | 5.37 × 10−4 | 1.63 × 10−7 | 0.85 (0.77–0.93) | 27,359,133–27,434,733 | IL4R, IL21R | |
A1, tested allele; CD, Crohn disease; CeD, coeliac disease; CI, confidence interval; MS, multiple sclerosis; OR, odds ratio in validation cohorts; Pso, psoriasis; RA, rheumatoid arthritis; SjS, Sjogren syndrome; SLE, systemic lupus erythematosus; SNP, single-nucleotide polymorphism; UC, ulcerative colitis.
PBC risk loci identified in the current study. SNPs were taken forward for validation based on having a discovery P value <2 × 10−5 (or, in the case of rs526231 and rs2434360, based on acting as a proxy for a SNP with a P value <2 × 10−5). Discovery P values were calculated using logistic regression of individual discovery data sets in ProbABEL followed by genomic control correction of individual discovery data sets in R and fixed-effects meta-analysis in META; validation P values were calculated using logistic regression of individual data sets in PLINK followed by fixed-effect meta-analysis in META; joint P values were calculated using fixed-effect meta-analysis of discovery and validation data sets in META; see Methods. Autoimmune overlap refers to overlap between risk loci for PBC and those of other autoimmune conditions.
*Functional annotation.
†Regulatory variants: The index SNP or variants in strong linkage disequilibrium (LD, r2≥0.8) with the index SNP at this locus overlap regulatory elements that are related to the annotated gene (Supplementary Table 3).
‡mQTLs: The index SNP or variants in strong LD are correlated to methylation related to the annotated gene (Supplementary Data 4).
§eQTLs: The index SNP or variants in strong LD are correlated to expression of the annotated gene (see Supplementary Data 3).