Genome-wide haplotype association analysis of primary biliary cholangitis risk in Japanese

Scientific Reports
Cindy ImYutaka Yasui

Abstract

Primary biliary cholangitis (PBC) susceptibility loci have largely been discovered through single SNP association testing. In this study, we report genic haplotype patterns associated with PBC risk genome-wide in two Japanese cohorts. Among the 74 genic PBC risk haplotype candidates we detected with a novel methodological approach in a discovery cohort of 1,937 Japanese, nearly two-thirds were replicated (49 haplotypes, Bonferroni-corrected P < 6.8 × 10-4) in an independent Japanese cohort (N = 949). Along with corroborating known PBC-associated loci (TNFSF15, HLA-DRA), risk haplotypes may potentially model cis-interactions that regulate gene expression. For example, one replicated haplotype association (9q32-9q33.1, OR = 1.7, P = 3.0 × 10-21) consists of intergenic SNPs outside of the human leukocyte antigen (HLA) region that overlap regulatory histone mark peaks in liver and blood cells, and are significantly associated with TNFSF8 expression in whole blood. We also replicated a novel haplotype association involving non-HLA SNPs mapped to UMAD1 (7p21.3; OR = 15.2, P = 3.9 × 10-9) that overlap enhancer peaks in liver and memory Th cells. Our analysis demonstrates the utility of haplotype association analyses in discovering and...Continue Reading

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Datasets Mentioned

BETA
GM12878
GM12891
GM12892
GM18951
EGAS00001002915

Methods Mentioned

BETA
ChIP-seq

Software Mentioned

Gviz
R “ LogicReg ”
Roadpmap
Roadmap
SHAPEIT
R “ haplo
R
HaploReg
. stats
ANNOVAR

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