A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors

Kyuto Sonehara; Yui Kimura; Yoshiko Nakano; Tatsuya Ozawa; Meiko Takahashi; Ken Suzuki; Takashi Fujii; Yuko Matsushita; Arata Tomiyama; Toshihiro Kishikawa; Kenichi Yamamoto; Tatsuhiko Naito; Tomonari Suzuki; Shigeru Yamaguchi; Tomoru Miwa; Hikaru Sasaki; Masashi Kitagawa; Naoyuki Ohe; Junya Fukai; Hideki Ogiwara; Atsufumi Kawamura; Satoru Miyawaki; Fumihiko Matsuda; Nobutaka Kiyokawa; Koichi Ichimura; Ryo Nishikawa; Yukinori Okada; Keita Terashima

doi:10.1038/s41467-022-32005-9

A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors

Kyuto Sonehara, Yui Kimura, Yoshiko Nakano, Tatsuya Ozawa, Meiko Takahashi, Ken Suzuki, Takashi Fujii, Yuko Matsushita, Arata Tomiyama, Toshihiro Kishikawa, Kenichi Yamamoto, Tatsuhiko Naito, Tomonari Suzuki, Shigeru Yamaguchi, Tomoru Miwa, Hikaru Sasaki, Masashi Kitagawa, Naoyuki Ohe, Junya Fukai, Hideki OgiwaraAtsufumi Kawamura, Satoru Miyawaki, Fumihiko Matsuda, Nobutaka Kiyokawa, Koichi Ichimura, Ryo Nishikawa, Yukinori Okada, Keita Terashima

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Abstract

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10⁻⁹, odds ratio = 2.46 [95% CI: 1.83–3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10⁻⁴, Spearman’s ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

Original language	English
Article number	4478
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32005-9
State	Published - Dec 2022
Externally published	Yes

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Sonehara, K., Kimura, Y., Nakano, Y., Ozawa, T., Takahashi, M., Suzuki, K., Fujii, T., Matsushita, Y., Tomiyama, A., Kishikawa, T., Yamamoto, K., Naito, T., Suzuki, T., Yamaguchi, S., Miwa, T., Sasaki, H., Kitagawa, M., Ohe, N., Fukai, J., ... Terashima, K. (2022). A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors. Nature Communications, 13(1), Article 4478. https://doi.org/10.1038/s41467-022-32005-9

@article{886ba58cf2af4e26841b31978bf5946e,

title = "A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors",

abstract = "Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10−9, odds ratio = 2.46 [95% CI: 1.83–3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10−4, Spearman{\textquoteright}s ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.",

author = "Kyuto Sonehara and Yui Kimura and Yoshiko Nakano and Tatsuya Ozawa and Meiko Takahashi and Ken Suzuki and Takashi Fujii and Yuko Matsushita and Arata Tomiyama and Toshihiro Kishikawa and Kenichi Yamamoto and Tatsuhiko Naito and Tomonari Suzuki and Shigeru Yamaguchi and Tomoru Miwa and Hikaru Sasaki and Masashi Kitagawa and Naoyuki Ohe and Junya Fukai and Hideki Ogiwara and Atsufumi Kawamura and Satoru Miyawaki and Fumihiko Matsuda and Nobutaka Kiyokawa and Koichi Ichimura and Ryo Nishikawa and Yukinori Okada and Keita Terashima",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-32005-9",

language = "English",

volume = "13",

journal = "Nature Communications",

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Sonehara, K, Kimura, Y, Nakano, Y, Ozawa, T, Takahashi, M, Suzuki, K, Fujii, T, Matsushita, Y, Tomiyama, A, Kishikawa, T, Yamamoto, K, Naito, T, Suzuki, T, Yamaguchi, S, Miwa, T, Sasaki, H, Kitagawa, M, Ohe, N, Fukai, J, Ogiwara, H, Kawamura, A, Miyawaki, S, Matsuda, F, Kiyokawa, N, Ichimura, K, Nishikawa, R, Okada, Y & Terashima, K 2022, 'A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors', Nature Communications, vol. 13, no. 1, 4478. https://doi.org/10.1038/s41467-022-32005-9

TY - JOUR

T1 - A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors

AU - Sonehara, Kyuto

AU - Kimura, Yui

AU - Nakano, Yoshiko

AU - Ozawa, Tatsuya

AU - Takahashi, Meiko

AU - Suzuki, Ken

AU - Fujii, Takashi

AU - Matsushita, Yuko

AU - Tomiyama, Arata

AU - Kishikawa, Toshihiro

AU - Yamamoto, Kenichi

AU - Naito, Tatsuhiko

AU - Suzuki, Tomonari

AU - Yamaguchi, Shigeru

AU - Miwa, Tomoru

AU - Sasaki, Hikaru

AU - Kitagawa, Masashi

AU - Ohe, Naoyuki

AU - Fukai, Junya

AU - Ogiwara, Hideki

AU - Kawamura, Atsufumi

AU - Miyawaki, Satoru

AU - Matsuda, Fumihiko

AU - Kiyokawa, Nobutaka

AU - Ichimura, Koichi

AU - Nishikawa, Ryo

AU - Okada, Yukinori

AU - Terashima, Keita

PY - 2022/12

Y1 - 2022/12

N2 - Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10−9, odds ratio = 2.46 [95% CI: 1.83–3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10−4, Spearman’s ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

AB - Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10−9, odds ratio = 2.46 [95% CI: 1.83–3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10−4, Spearman’s ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

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U2 - 10.1038/s41467-022-32005-9

DO - 10.1038/s41467-022-32005-9

M3 - Article

AN - SCOPUS:85135212976

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4478

ER -

A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors

Abstract

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