TY - JOUR
T1 - Integration of genetics and miRNA–target gene network identified disease biology implicated in tissue specificity
AU - Sakaue, Saori
AU - Hirata, Jun
AU - Maeda, Yuichi
AU - Kawakami, Eiryo
AU - Nii, Takuro
AU - Kishikawa, Toshihiro
AU - Ishigaki, Kazuyoshi
AU - Terao, Chikashi
AU - Suzuki, Ken
AU - Akiyama, Masato
AU - Suita, Naomasa
AU - Masuda, Tatsuo
AU - Ogawa, Kotaro
AU - Yamamoto, Kenichi
AU - Saeki, Yukihiko
AU - Matsushita, Masato
AU - Yoshimura, Maiko
AU - Matsuoka, Hidetoshi
AU - Ikari, Katsunori
AU - Taniguchi, Atsuo
AU - Yamanaka, Hisashi
AU - Kawaji, Hideya
AU - Lassmann, Timo
AU - Itoh, Masayoshi
AU - Yoshitomi, Hiroyuki
AU - Ito, Hiromu
AU - Ohmura, Koichiro
AU - Forrest, Alistair R.R.
AU - Hayashizaki, Yoshihide
AU - Carninci, Piero
AU - Kumanogoh, Atsushi
AU - Kamatani, Yoichiro
AU - de Hoon, Michiel
AU - Yamamoto, Kazuhiko
AU - Okada, Yukinori
N1 - Funding Information:
Japan Society for the Promotion of Science (JSPS) KAK-ENHI [15H05670, 15H05911, 15K14429, 16KT0196]; Japan Agency for Medical Research and Development [17ek0410047h0001, 18gm6010001h0003, 18ek0410041h0002]; Takeda Science Foundation; Naka-jima Foundation; SECOM Science and Technology Foundation, Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Bioinformat-ics Initiative of Osaka University Graduate School of Medicine, and Inoue Foundation for Science. FANTOM5 was made possible by a Research Grant for RIKEN Omics Science Center from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Y.H.); MEXT for the RIKEN Preventive Medicine and Diagnosis Innovation Program (to Y.H.); Grant of the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from the MEXT, Japan (to Y.H.); Grant from MEXT to the RIKEN Center for Life Science Technologies and Grant from MEXT to RIKEN Center for Integrative Medical Sciences; J.H. is an employee of TEIJIN PHARMA LIMITED; N.S. is an employee of Ono Pharmaceutical Co., Ltd. Funding for open access charge: Japan Agency for Medical Research and Development [18ek0410041h0002]. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2018/12/14
Y1 - 2018/12/14
N2 - 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 (∼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 (nTotal = 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 × 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.
AB - 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 (∼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 (nTotal = 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 × 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.
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U2 - 10.1093/nar/gky1066
DO - 10.1093/nar/gky1066
M3 - Article
C2 - 30407537
AN - SCOPUS:85058920372
SN - 0305-1048
VL - 46
SP - 11898
EP - 11909
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 22
ER -
