Genetic investigation into an increased susceptibility to biliary atresia in an extended New Zealand Maori family

Cameron-Christie, SR; Wilde, J; Gray, A; Tankard, R; Bahlo, M; Markie, D; Evans, HM; Robertson, SP

Author(s): Cameron-Christie, SR; Wilde, J; Gray, A; Tankard, R; Bahlo, M; Markie, D; Evans, HM; Robertson, SP;
Details: Publication Year 2018-12-18,Volume 11,Issue #1,Page 121
Journal Title: BMC Med Genomics
Publication Type: Journal Article
Abstract: BACKGROUND: Biliary atresia (BA), a fibrosing disorder of the developing biliary tract leading to liver failure in infancy, has an elevated incidence in indigenous New Zealand (NZ) Maori. We investigated a high rate of BA in a group of children (n = 12) belonging to a single Maori iwi (or 'tribe', related through a remote ancestor). METHODS: Population and geographical data was used to estimate the rate of BA in Maori sub-groups, and a pedigree linking most of the affected children was constructed from oral and documented history. Array genotyping was used to examine hypotheses about the inheritance of a possible genetic risk factor, and the history of the affected population, and Exome Sequencing to search for candidate genes. RESULTS: Most of these affected children (n = 7) link to a self-reported pedigree and carry a 50-fold increase in BA risk over unrelated Maori (chi(2) = 296P < 0.001, 95% CI 23-111). Genetic analysis using FEstim and SNP array genotypes revealed no evidence for elevated consanguinity between parents of affected children (FEstim: F (2,21) = 0.469, P > 0.63). Genome-wide quantitation of intervals of contiguous, homozygous-by-state markers reached a similar conclusion (F (2,399) = 1.99, P = 0.138). Principal component analysis and investigation with STRUCTURE found no evidence of increased allele frequency of either a recessive variant, or additive, low-risk variants due to reproductive isolation. To identify candidate causal factors, Exome Sequencing datasets were scrutinised for shared rare coding variants across 8 affected individuals. No rare, non-synonymous, phylogenetically conserved variants were common to 6 or more affected children. CONCLUSION: The substantially elevated risk for development of BA in this subgroup could be mediated by genetic factors, but the iwi exhibits no properties indicative of recent or remote reproductive isolation. Resolution of any risk loci may rely on extensive genomic sequencing studies in this iwi or investigation of other mechnaisms such as copy number variation.
Publisher: BMC
Research Division(s): Population Health And Immunity
PubMed ID: 30563518
Publisher's Version: https://doi.org/10.1186/s12920-018-0440-0
Open Access at Publisher's Site: https://doi.org/10.1186/s12920-018-0440-0
NHMRC Grants: NHMRC/1002098, NHMRC/1054618,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2019-01-15 09:07:41

Last Modified: 2019-01-15 09:15:32