Integration of genetics and miRNA-target gene network identified disease biology implicated in tissue specificity

被引：36

作者：

Sakaue, Saori ^{[1
,2
,3
]}

Hirata, Jun ^{[1
,4
]}

Maeda, Yuichi ^{[5
,6
,7
]}

Kawakami, Eiryo ^{[8
,9
]}

Nii, Takuro ^{[5
,6
,7
]}

Kishikawa, Toshihiro ^{[1
,10
]}

Ishigaki, Kazuyoshi ^{[2
]}

Terao, Chikashi ^{[2
,11
,12
,13
]}

Suzuki, Ken ^{[1
,2
]}

Akiyama, Masato ^{[2
,14
]}

Suita, Naomasa ^{[1
,15
]}

Masuda, Tatsuo ^{[1
,16
]}

Ogawa, Kotaro ^{[1
,17
]}

Yamamoto, Kenichi ^{[1
,18
]}

Saeki, Yukihiko ^{[19
]}

Matsushita, Masato ^{[20
,21
]}

Yoshimura, Maiko ^{[21
]}

Matsuoka, Hidetoshi ^{[21
]}

Ikari, Katsunori ^{[22
,23
]}

Taniguchi, Atsuo ^{[22
]}

Yamanaka, Hisashi ^{[22
]}

Kawaji, Hideya ^{[24
,25
,26
,27
]}

Lassmann, Timo ^{[24
,25
,28
]}

Itoh, Masayoshi ^{[24
,25
,26
]}

Yoshitomi, Hiroyuki ^{[29
,30
]}

Ito, Hiromu ^{[30
]}

Ohmura, Koichiro ^{[13
]}

Forrest, Alistair R. R. ^{[24
,25
,31
,32
]}

Hayashizaki, Yoshihide ^{[25
,26
]}

Carninci, Piero ^{[24
,25
,33
]}

Kumanogoh, Atsushi ^{[5
]}

Kamatani, Yoichiro ^{[2
,34
]}

de Hoon, Michiel ^{[24
,25
,35
]}

Yamamoto, Kazuhiko ^{[36
]}

Okada, Yukinori ^{[1
,2
,37
]}

机构：

[1] Osaka Univ, Grad Sch Med, Dept Stat Genet, Suita, Osaka 5650871, Japan

[2] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa 2300045, Japan

[3] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Tokyo 1138655, Japan

[4] TEIJIN PHARMA LTD, Pharmaceut Discovery Res Labs, Hino, Tokyo 1918512, Japan

[5] Osaka Univ, Grad Sch Med, Dept Resp Med & Clin Immunol, WPI Immunol Frontier Res Ctr, Suita, Osaka 5650871, Japan

[6] Osaka Univ, Grad Sch Med, Dept Microbiol & Immunol, WPI Immunol Frontier Res Ctr,Lab Immune Regulat, Suita, Osaka 5650871, Japan

[7] Japan Agcy Med Res & Dev, Core Res Evolut Sci & Technol, Tokyo 1000004, Japan

[8] RIKEN, Med Sci Innovat Hub Program MIH, Healthcare & Med Data Driven Based Predict Reason, Yokohama, Kanagawa 2300045, Japan

[9] RIKEN, Ctr Integrat Med Sci, Lab Dev Genet, Yokohama, Kanagawa 2300045, Japan

[10] Osaka Univ, Grad Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Suita, Osaka 5650871, Japan

[11] Shizuoka Prefectural Gen Hosp, Clin Res Ctr, Shizuoka 4200881, Japan

[12] Univ Shizuoka, Sch Pharmaceut Sci, Shizuoka 4228526, Japan

[13] Kyoto Univ, Grad Sch Med, Dept Rheumatol & Clin Immunol, Kyoto 6068507, Japan

[14] Kyushu Univ, Grad Sch Med Sci, Dept Ophthalmol, Fukuoka, Fukuoka 8128582, Japan

[15] Ono Pharmaceut Co Ltd, Tsukuba Res Inst, Discovery Technol Res Labs, Tsukuba, Ibaraki 3004247, Japan

[16] Osaka Univ, Grad Sch Med, Dept Obstet & Gynecol, Suita, Osaka 5650871, Japan

[17] Osaka Univ, Grad Sch Med, Dept Neurol, Suita, Osaka 5650871, Japan

[18] Osaka Univ, Grad Sch Med, Dept Pediat, Suita, Osaka 5650871, Japan

[19] Osaka Minami Med Ctr, NHO, Dept Clin Res, Kawachi Nagano, Japan

[20] Saiseikai Senri Hosp, Dept Rheumatol & Allergol, Suita, Osaka 5650862, Japan

[21] Osaka Minami Med Ctr, NHO, Dept Rheumatol & Allergol, Kawachi Nagano, Japan

[22] Tokyo Womens Med Univ, Inst Rheumatol, Tokyo 1620054, Japan

[23] Japan Sci & Technol Agcy JST, CREST, Tokyo 1620054, Japan

[24] RIKEN, Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa 2300045, Japan

[25] RIKEN, OSC, Yokohama, Kanagawa 2300045, Japan

[26] RIKEN, Prevent Med & Diag Innovat Program PMI, Saitama 3510198, Japan

[27] RIKEN, Ctr Integrat Med Sci, Prevent Med & Appl Genom Unit, Yokohama, Kanagawa 2300045, Japan

[28] Univ Western Australia, Telethon Kids Inst, Subiaco, WA 6008, Australia

[29] Kyoto Univ, Inst Frontier Life & Med Sci, Dept Regenerat Sci & Engn, Lab Tissue Regenerat, Kyoto 6068507, Japan

[30] Kyoto Univ, Grad Sch Med, Dept Orthopaed Surg, Kyoto 6068507, Japan

[31] Univ Western Australia, Harry Perkins Inst Med Res, QEII Med Ctr, Nedlands, WA 6009, Australia

[32] Univ Western Australia, Ctr Med Res, Nedlands, WA 6009, Australia

[33] RIKEN, Ctr Integrat Med Sci, Lab Transcriptome Technol, Yokohama, Kanagawa 2300045, Japan

[34] Kyoto Univ, Grad Sch Med, Kyoto McGill Int Collaborat Sch Genom Med, Kyoto 6068507, Japan

[35] RIKEN, Ctr Integrat Med Sci, Lab Appl Computat Genom, Yokohama, Kanagawa 2300045, Japan

[36] RIKEN, Ctr Integrat Med Sci, Lab Autoimmune Dis, Yokohama, Kanagawa 2300045, Japan

[37] Osaka Univ, Immunol Frontier Res Ctr WPI IFReC, Lab Stat Immunol, Suita, Osaka 5650871, Japan

来源：

NUCLEIC ACIDS RESEARCH | 2018年 / 46卷 / 22期

基金：

日本学术振兴会;

关键词：

EXPRESSION; RISK; GWAS; HERITABILITY; ARCHITECTURE; MICRORNAS; RESOURCE; PROJECT;

D O I：

10.1093/nar/gky1066

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA-target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (similar to 1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA-target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (eta(Total) = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 x 10(-8)). Our result highlighted that miRNA-target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers.

引用

页码：11898 / 11909

页数：12

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