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Updated: Dec 8, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Whole-exome sequencing reveals ANO8 as a genetic risk factor for intrahepatic cholestasis of pregnancy
Xianxian Liu1,2, Hua Lai1,3, Xiaoming Zeng1,3
1Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, 330006, Nanchang, Jiangxi, China.
Insights
This study identifies novel genetic variants in genes like ABCB4, ABCB11, and ANO8 associated with intrahepatic cholestasis of pregnancy (ICP). These findings enhance our understanding of ICP's genetic basis and potential diagnostic markers.
Area of Science:
- Genetics
- Hepatology
- Obstetrics
Background:
- Intrahepatic cholestasis of pregnancy (ICP) causes adverse pregnancy outcomes.
- The genetic factors contributing to ICP remain largely unknown.
- Understanding ICP genetics is crucial for improving maternal and fetal health.
Purpose of the Study:
- To investigate the genetic architecture of intrahepatic cholestasis of pregnancy (ICP).
- To identify novel genetic loci associated with ICP in a Chinese cohort.
- To explore the role of specific genes, such as ANO8, in ICP pathogenesis.
Main Methods:
- Whole-exome sequencing (WES) was performed on 151 Chinese ICP patients.
- Bioinformatic analyses included variant calling, annotation, and functional predictions.
- Statistical analyses (t-test, Fisher's test, ROC curves) were used to assess variant significance and clinical correlations.
Main Results:
- Eighteen potential pathogenic loci in known ICP-associated genes (ABCB4, ABCB11, ATP8B1, TJP2) were identified.
- The gene ANO8, involved in bile salt transport, was newly associated with ICP, with 8 rare missense mutations found in patients.
- ICP patients with ANO8 mutations exhibited significantly higher total bile acid levels compared to wild-type individuals.
Conclusions:
- This is the first study utilizing WES to detect genetic loci for ICP.
- The identified genetic variants provide new insights into the genetic basis of ICP.
- These findings may aid in the future identification of mutations underlying ICP.
Background:
Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and cholestasis in late pregnancy and results in adverse pregnancy outcomes, including preterm delivery and birth weight, which are affected by the genetic and environmental background. However, until now, the genetic architecture of ICP has remained largely unclear.
Methods:
Twenty-six clinical data points were recorded for 151 Chinese ICP patients. The data generated from whole-exome sequencing (WES) using the BGISEQ-500 platform were further analyzed by Burrows-Wheeler Aligner (BWA) software, Genome Analysis Toolkit (GATK), ANNOVAR tool, etc. R packages were used to conduct t-test, Fisher's test and receiver operating characteristic (ROC) curve analyses.
Results:
We identified eighteen possible pathogenic loci associated with ICP disease in known genes, covering ABCB4, ABCB11, ATP8B1 and TJP2. The loci Lys386Gln, Gly527Gln and Trp708Ter in ABCB4, Leu589Met, Gln605Pro and Gln1194Ter in ABCB11, and Arg189Ser in TJP2 were novel discoveries. In addition, WES analysis indicated that the gene ANO8 involved in the transport of bile salts is newly identified as associated with ICP. The functional network of the ANO8 gene confirmed this finding. ANO8 contained 8 rare missense mutations that were found in eight patients among the 151 cases and were absent from 1029 controls. Out of the eight SNPs, 3 were known, and the remaining five are newly identified. These variants have a low frequency, ranging from 0.000008 to 0.00001 in the ExAC, gnomAD - Genomes and TOPMED databases. Bioinformatics analysis showed that the sites and their corresponding amino acids were both highly conserved among vertebrates. Moreover, the influences of all the mutations on protein function were predicted to be damaging by the SIFT tool. Combining clinical data, it was found that the mutation group (93.36 µmol/L) had significantly (P = 0.038) higher total bile acid (TBA) levels than the wild-type group (40.81 µmol/L).
Conclusions:
To the best of our knowledge, this is the first study to employ WES technology to detect genetic loci for ICP. Our results provide new insights into the genetic basis of ICP and will benefit the final identification of the underlying mutations.
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