Expression quantitative trait locus mapping of extracellular microRNAs in human plasma

Tianxiao Huan; Roby Joehanes; Jian Rong; Ming-Huei Chen; Rima Mustafa; Abbas Dehghan; Mohsen Ghanbari; Hannah Karlin; Shih-Jen Hwang; Paul Courchesne; Martin G Larson; Andrew D Johnson; Jane E Freedman; Daniel Levy

doi:10.1016/j.isci.2024.110988

Expression quantitative trait locus mapping of extracellular microRNAs in human plasma

iScience. 2024 Sep 18;27(10):110988. doi: 10.1016/j.isci.2024.110988. eCollection 2024 Oct 18.

Authors

Tianxiao Huan^{1

2}, Roby Joehanes^{1

2}, Jian Rong³, Ming-Huei Chen^{1

2}, Rima Mustafa⁴, Abbas Dehghan^{4

5}, Mohsen Ghanbari⁶, Hannah Karlin^{1

2}, Shih-Jen Hwang^{1

2}, Paul Courchesne^{1

2}, Martin G Larson³, Andrew D Johnson^{1

2}, Jane E Freedman⁷, Daniel Levy^{1

2}

Affiliations

¹ The National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA 01702, USA.
² The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20824, USA.
³ Department of Mathematics and Statistics, Boston University, Boston, MA 02118, USA.
⁴ Department of Epidemiology and Biostatistics, Imperial College London, London SW7 2AZ, UK.
⁵ MRC Centre for Environment and Health, Imperial College London, London SW7 2AZ, UK.
⁶ Department of Epidemiology, Erasmus MC University Medical Center, 3000 CA Rotterdam, the Netherlands.
⁷ School of Medicine, Vanderbilt University, 1161 21st Avenue S, Nashville, TN 37232, USA.

Abstract

MicroRNAs, crucial in regulating protein-coding gene expression, are implicated in various diseases. We performed a genome-wide association study of plasma miRNAs (ex-miRNAs) in 3,743 Framingham Heart Study (FHS) participants and identified 1,027 cis-ex-miRNA-eQTLs (cis-exQTLs) for 37 ex-miRNAs, with 55% replication in an independent study. Colocalization analyses suggested potential genetic coregulation of ex-miRNAs with whole blood mRNAs. Mendelian randomization indicated 29 ex-miRNAs potentially influencing 35 traits. Notably, the chromosome 14q23 and 14q32 miRNA clusters emerged as the top signal, contributing over 50% of the significant cis-exQTL results, and were associated with a diverse range of traits including platelet count. Correlations of 10 ex-miRNAs (such as miR-376c-3p) in 14q32 with platelet count and volume were confirmed in FHS participants. These findings shed light on the genetic basis of ex-miRNA expression and their involvement in complex traits.

Keywords: Association analysis; Body substance sample; Genomics; Quantitative genetics; Transcriptomics.