1. Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes
- Author
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Glessner, Joseph T, Ningappa, Mylarappa B, Ngo, Kim A, Zahid, Maliha, So, Juhoon, Higgs, Brandon W, Sleiman, Patrick MA, Narayanan, Tejaswini, Ranganathan, Sarangarajan, March, Michael, Prasadan, Krishna, Vaccaro, Courtney, Reyes-Mugica, Miguel, Velazquez, Jeremy, Salgado, Claudia M, Ebrahimkhani, Mo R, Schmitt, Lori, Rajasundaram, Dhivyaa, Paul, Morgan, Pellegrino, Renata, Gittes, George K, Li, Dong, Wang, Xiang, Billings, Jonathan, Squires, Robert, Ashokkumar, Chethan, Sharif, Khalid, Kelly, Deirdre, Dhawan, Anil, Horslen, Simon, Lo, Cecilia W, Shin, Donghun, Subramaniam, Shankar, Hakonarson, Hakon, and Sindhi, Rakesh
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Digestive Diseases ,Human Genome ,Congenital Structural Anomalies ,Prevention ,Liver Disease ,Infant Mortality ,Pediatric ,Rare Diseases ,Perinatal Period - Conditions Originating in Perinatal Period ,Chronic Liver Disease and Cirrhosis ,Aetiology ,2.1 Biological and endogenous factors ,Child ,Animals ,Mice ,Humans ,Biliary Atresia ,Genome-Wide Association Study ,Genetic Predisposition to Disease ,Zebrafish ,Canada ,Ciliogenesis ,Polygenic Susceptibility ,Portal Vein ,Tube Morphogenesis ,Vascular Development ,Public Health and Health Services ,Gastroenterology & Hepatology ,Clinical sciences - Abstract
Background & aimsBiliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA.MethodsWe performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models.ResultsA GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency
- Published
- 2023