Volume 53, Issue 11 pp. 1134-1141

SHORT COMMUNICATION

Rare sequence variants associated with the risk of non-syndromic biliary atresia

Satoshi Tamaoka,

Satoshi Tamaoka

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

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Akinari Fukuda,

Akinari Fukuda

Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan

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Kazuhiko Nakabayashi,

Kazuhiko Nakabayashi

Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan

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Keiko Matsubara,

Keiko Matsubara

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

Division of Diversity Research, National Center for Child Health and Development, Tokyo, Japan

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Hiroko Ogata-Kawata,

Hiroko Ogata-Kawata

Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan

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Yuki Muranishi,

Yuki Muranishi

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

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Kenichiro Hata,

Kenichiro Hata

Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan

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Yuko Kato-Fukui,

Yuko Kato-Fukui

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

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Seisuke Sakamoto,

Seisuke Sakamoto

Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan

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Mureo Kasahara,

Mureo Kasahara

Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan

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Maki Fukami,

Corresponding Author

Maki Fukami

[email protected]

orcid.org/0000-0001-9971-4035

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

Division of Diversity Research, National Center for Child Health and Development, Tokyo, Japan

Correspondence

Maki Fukami, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.

Email: [email protected]

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Satoshi Tamaoka,

Satoshi Tamaoka

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

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Akinari Fukuda,

Akinari Fukuda

Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan

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Kazuhiko Nakabayashi,

Kazuhiko Nakabayashi

Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan

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Keiko Matsubara,

Keiko Matsubara

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

Division of Diversity Research, National Center for Child Health and Development, Tokyo, Japan

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Hiroko Ogata-Kawata,

Hiroko Ogata-Kawata

Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan

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Yuki Muranishi,

Yuki Muranishi

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

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Kenichiro Hata,

Kenichiro Hata

Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan

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Yuko Kato-Fukui,

Yuko Kato-Fukui

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

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Seisuke Sakamoto,

Seisuke Sakamoto

Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan

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Mureo Kasahara,

Mureo Kasahara

Center for Organ Transplantation, National Center for Child Health and Development, Tokyo, Japan

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Maki Fukami,

Corresponding Author

Maki Fukami

[email protected]

orcid.org/0000-0001-9971-4035

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

Division of Diversity Research, National Center for Child Health and Development, Tokyo, Japan

Correspondence

Maki Fukami, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan.

Email: [email protected]

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First published: 25 July 2023

https://doi.org/10.1111/hepr.13946

Citations: 1

This study met ethics and integrity policies of Hepatology Research.

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Abstract

Aim

The etiology of non-syndromic biliary atresia (BA) remains largely unknown. In this study, we performed genome-wide screening of genes associated with the risk of non-syndromic BA.

Methods

We analyzed exome data of 15 Japanese patients with non-syndromic BA and 509 control individuals using an optimal sequence kernel association test (SKAT-O), a gene-based association study optimized for small-number subjects. Furthermore, we examined the frequencies of known BA-related single-nucleotide polymorphisms in the BA and control groups.

Results

SKAT-O showed that rare damaging variants of MFHAS1, a ubiquitously expressed gene encoding a Toll-like receptor-associated protein, were more common in the BA group than in the control group (Bonferroni corrected p-value = 0.0097). Specifically, p.Val106Gly and p.Arg556Cys significantly accumulated in the patient group. These variants resided within functionally important domains. SKAT-O excluded the presence of other genes significantly associated with the disease risk. Of 60 known BA-associated single-nucleotide polymorphisms, only eight were identified in the BA group. In particular, p.Ile3421Met of MYO15A and p.Ala421Thr of THOC2 were more common in the BA group than in the control group. However, the significance of these two variants is questionable, because MYO15A has been linked to deafness, but not to BA, and the p.Ala421Thr of THOC2 represents a relatively common single-nucleotide polymorphism in Asia.

Conclusions

The results of this study indicate that rare damaging variants in MFHAS1 may constitute a risk factor for non-syndromic BA, whereas the contribution of other monogenic variants to the disease predisposition is limited.

Graphical Abstract

We conducted an optimal sequence kernel association test using exome data of 15 Japanese patients with non-syndromic type III biliary atresia and 509 control individuals. The results indicate that rare damaging variants in MFHAS1 may constitute a risk factor for non-syndromic biliary atresia; however, the overall contribution of monogenic variants to the disease predisposition is small.

CONFLICT OF INTEREST STATEMENT

Authors declare no Conflict of Interests for this article.

Open Research

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author on request.

Supporting Information

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Citing Literature

Volume53, Issue11

November 2023

Pages 1134-1141

Filename	Description
hepr13946-sup-0001-table_s1.xlsx15.1 KB	Table S1
hepr13946-sup-0002-table_s2.xlsx14.1 KB	Table S2