Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep19877
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Funding
- Wellcome Trust [076113]
- Foundation for the Author of National Excellent Doctoral Dissertatio n of PR China [201325]
- National Natural Science Foundation of China [81170380, 81325002, 81400608, 81570469]
- Innovation Program of Shanghai Jiao Tong University [YG2014MS43]
- National Institutes of Health [R01DK091823, R01AR065174, K08AR057763]
- MRC [G1001799, MR/N01104X/1] Funding Source: UKRI
- Medical Research Council [MR/N01104X/1, G1001799] Funding Source: researchfish
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Primary biliary cirrhosis (PBC), a chronic autoimmune liver disease, has been associated with increased incidence of osteoporosis. Intriguingly, two PBC susceptibility loci identified through genome-wide association studies are also involved in bone mineral density (BMD). These observations led us to investigate the genetic variants shared between PBC and BMD. We evaluated 72 genome-wide significant BMD SNPs for association with PBC using two European GWAS data sets (n = 8392), with replication of significant findings in a Chinese cohort (685 cases, 1152 controls). Our analysis identified a novel variant in the intron of the CLDN14 gene (rs170183, P-fdr = 0.015) after multiple testing correction. The three associated variants were followed-up in the Chinese cohort; one SNP rs170183 demonstrated consistent evidence of association in diverse ethnic populations (P-combined = 2.43 x 10(-5)). Notably, expression quantitative trait loci (eQTL) data revealed that rs170183 was correlated with a decline in CLDN14 expression in both lymphoblastoid cell lines and T cells (P-adj = 0.003 and 0.016, respectively). In conclusion, our study identified a novel PBC susceptibility variant that has been shown to be strongly associated with BMD, highlighting the potential of pleiotropy to improve gene discovery.
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