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Genetic architecture of microRNA expression and its link to complex diseases in the Japanese population.

Authors
  • Sonehara, Kyuto1, 2
  • Sakaue, Saori1, 3, 4, 5, 6
  • Maeda, Yuichi2, 7, 8
  • Hirata, Jun1, 9
  • Kishikawa, Toshihiro1, 10, 11
  • Yamamoto, Kenichi1, 12, 13
  • Matsuoka, Hidetoshi14
  • Yoshimura, Maiko14
  • Nii, Takuro7, 8
  • Ohshima, Shiro14
  • Kumanogoh, Atsushi2, 7, 15
  • Okada, Yukinori1, 2, 13, 16, 17
  • 1 Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. , (Japan)
  • 2 Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita 565-0871, Japan. , (Japan)
  • 3 Center for Data Sciences, Harvard Medical School, Boston, MA 02114, USA.
  • 4 Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 6 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. , (Japan)
  • 7 Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. , (Japan)
  • 8 Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. , (Japan)
  • 9 Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, Hino 191-8512, Japan. , (Japan)
  • 10 Department of Otorhinolaryngology - Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. , (Japan)
  • 11 Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan. , (Japan)
  • 12 Department of Pediatrics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. , (Japan)
  • 13 Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita 565-0871, Japan. , (Japan)
  • 14 Rheumatology and Allergology, NHO Osaka Minami Medical Center, Kawachinagano 586-8521, Japan. , (China)
  • 15 Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita 565-0871, Japan. , (Japan)
  • 16 The Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita 565-0871, Japan. , (Japan)
  • 17 Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. , (Japan)
Type
Published Article
Journal
Human Molecular Genetics
Publisher
Oxford University Press
Publication Date
Jun 04, 2022
Volume
31
Issue
11
Pages
1806–1820
Identifiers
DOI: 10.1093/hmg/ddab361
PMID: 34919704
Source
Medline
Language
English
License
Unknown

Abstract

Understanding the genetic effects on non-coding RNA (ncRNA) expression facilitates functional characterization of disease-associated genetic loci. Among several classes of ncRNAs, microRNAs (miRNAs) are key post-transcriptional gene regulators. Despite its biological importance, previous studies on the genetic architecture of miRNA expression focused mostly on the European individuals, underrepresented in other populations. Here, we mapped miRNA expression quantitative trait loci (miRNA-eQTL) for 343 miRNAs in 141 Japanese using small RNA sequencing and whole-genome sequencing, identifying 1275 cis-miRNA-eQTL variants for 40 miRNAs (false discovery rate < 0.2). Of these, 25 miRNAs having eQTL were unreported in the European studies, including 5 miRNAs with their lead variant monomorphic in the European populations, which demonstrates the value of miRNA-eQTL analysis in diverse ancestral populations. MiRNAs with eQTL effect showed allele-specific expression (ASE; e.g. miR-146a-3p), and ASE analysis further detected cis-regulatory variants not captured by the conventional miRNA-eQTL mapping (e.g. miR-933). We identified a copy number variation associated with miRNA expression (e.g. miR-570-3p, P = 7.2 × 10-6), which contributes to a more comprehensive landscape of miRNA-eQTLs. To elucidate a post-transcriptional modification in miRNAs, we created a catalog of miRNA-editing sites, including 10 canonical and 6 non-canonical sites. Finally, by integrating the miRNA-eQTLs and Japanese genome-wide association studies of 25 complex traits (mean n = 192 833), we conducted a transcriptome-wide association study, identifying miR-1908-5p as a potential mediator for adult height, colorectal cancer and type 2 diabetes (P < 9.1 × 10-5). Our study broadens the population diversity in ncRNA-eQTL studies and contributes to functional annotation of disease-associated loci found in non-European populations. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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