Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome
Xiaoyuan Jia, Tomohiko Yamamura, Rasheed Gbadegesin, Michelle T. McNulty, Kyuyong Song, China Nagano, Yuki Hitomi, Dongwon Lee, Yoshihiro Aiba, Seik‐Soon Khor, Kazuko Ueno, Yosuke Kawai, Masao Nagasaki, Eisei Noiri, Tomoko Horinouchi, Hiroshi Kaito, Riku Hamada, Takayuki Okamoto, Koichi Kamei, Yoshitsugu Kaku, Rika Fujimaru, Ryojiro Tanaka, Yuko Shima, Yoshinori Araki, Yoshinobu Nagaoka, Takayuki Okamoto, Yasuyuki Sato, Asako Hayashi, Toshiyuki Takahashi, Hayato Aoyagi, Michihiko Ueno, Masanori Nakanishi, Nariaki Toita, Kimiaki Uetake, Norio Kobayashi, Shoji Fujita, Kazushi Tsuruga, Naonori Kumagai, Hiroki Kudo, Eriko Tanaka, Tae Omori, Mari Okada, Yoshiho Hatai, Tomohiro Udagawa, Yaeko Motoyoshi, Kenji Ishikura, Koichi Kamei, Masao Ogura, Mai Sato, Yuji Kano, Motoshi Hattori, Kenichiro Miura, Yutaka Harita, Shoichiro Kanda, Emi Sawanobori, Anna Kobayashi, Manabu Kojika, Yoko Ohwada, Kunimasa Yan, Hiroshi Hataya, Riku Hamada, Chikako Terano, Ryoko Harada, Yuko Hamasaki, Junya Hashimoto, Shuichi Ito, Hiroyuki Machida, Aya Inaba, Takeshi Matsuyama, Miwa Goto, Masaki Shimizu, Kazuhide Ohta, Yohei Ikezumi, Takeshi Yamada, Toshiaki Suzuki, Soichi Tamamura, Yukiko Mori, Yoshihiko Hidaka, Daisuke Matsuoka, Tatsuya Kinoshita, Shunsuke Noda, Masashi Kitahara, Naoya Fujita, Satoshi Hibino, Kazumoto Iijima, Kandai Nozu, Hiroshi Kaito, Shogo Minamikawa, Tomohiko Yamamura, China Nagano, Tomoko Horinouchi, Keita Nakanishi, Junya Fujimura, Nana Sakakibara, Yuya Aoto, Shinya Ishiko, Ryojiro Tanaka, Kyoko Kanda, Yosuke Inaguma, Yuya Hashimura
Abstract
To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (P meta =6.71E-28, OR=1.88) and TNFSF15 (P meta =5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).