A comprehensive study of genetic regulation and disease associations of plasma circulatory microRNAs using population-level data.

Autor: Mustafa R; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; UK Dementia Research Institute, Imperial College London, London, UK.; Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UK., Mens MMJ; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Social and Behavorial Sciences, Harvard T.H Chan School of Public Health, Boston, MA, USA., van Hilten A; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., Huang J; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.; Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore., Roshchupkin G; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., Huan T; Framingham Heart Study, Framingham, MA, USA.; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Broer L; Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., van Meurs JBJ; Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Orthopaedics and Sports Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., Elliott P; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; UK Dementia Research Institute, Imperial College London, London, UK.; MRC Centre for Environment and Health, Imperial College London, London, UK.; Health Data Research (HDR) UK, Imperial College London, London, UK.; BHF Centre for Research Excellence, Imperial College London, London, UK., Levy D; Framingham Heart Study, Framingham, MA, USA.; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Ikram MA; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., Evangelou M; Department of Mathematics, Imperial College London, London, UK., Dehghan A; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.; UK Dementia Research Institute, Imperial College London, London, UK.; MRC Centre for Environment and Health, Imperial College London, London, UK., Ghanbari M; Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. m.ghanbari@erasmusmc.nl.
Jazyk: angličtina
Zdroj: Genome biology [Genome Biol] 2024 Oct 21; Vol. 25 (1), pp. 276. Date of Electronic Publication: 2024 Oct 21.
DOI: 10.1186/s13059-024-03420-6
Abstrakt: Background: MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Perturbations in plasma miRNA levels are known to impact disease risk and have potential as disease biomarkers. Exploring the genetic regulation of miRNAs may yield new insights into their important role in governing gene expression and disease mechanisms.
Results: We present genome-wide association studies of 2083 plasma circulating miRNAs in 2178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We identify 3292 associations between 1289 SNPs and 63 miRNAs, of which 65% are replicated in two independent cohorts. We demonstrate that plasma miR-eQTLs co-localise with gene expression, protein, and metabolite-QTLs, which help in identifying miRNA-regulated pathways. We investigate consequences of alteration in circulating miRNA levels on a wide range of clinical conditions in phenome-wide association studies and Mendelian randomisation using the UK Biobank data (N = 423,419), revealing the pleiotropic and causal effects of several miRNAs on various clinical conditions. In the Mendelian randomisation analysis, we find a protective causal effect of miR-1908-5p on the risk of benign colon neoplasm and show that this effect is independent of its host gene (FADS1).
Conclusions: This study enriches our understanding of the genetic architecture of plasma miRNAs and explores the signatures of miRNAs across a wide range of clinical conditions. The integration of population-based genomics, other omics layers, and clinical data presents opportunities to unravel potential clinical significance of miRNAs and provides tools for novel miRNA-based therapeutic target discovery.
(© 2024. The Author(s).)
Databáze: MEDLINE
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