MicroRNA-eQTLs in the developing human neocortex link miR-4707-3p expression to brain size
Abstract
Expression quantitative trait loci (eQTL) data have proven important for linking non-coding loci to protein-coding genes. But eQTL studies rarely measure microRNAs (miRNAs), small non-coding RNAs known to play a role in human brain development and neurogenesis. Here, we performed small-RNA sequencing across 212 mid-gestation human neocortical tissue samples, measured 907 expressed miRNAs, discovering 111 of which were novel, and identified 85 local-miRNA-eQTLs. Colocalization of miRNA-eQTLs with GWAS summary statistics yielded one robust colocalization of miR-4707-3p expression with educational attainment and brain size phenotypes, where the miRNA expression increasing allele was associated with decreased brain size. Exogenous expression of miR-4707-3p in primary human neural progenitor cells decreased expression of predicted targets and increased cell proliferation, indicating miR-4707-3p modulates progenitor gene regulation and cell fate decisions. Integrating miRNA-eQTLs with existing GWAS yielded evidence of a miRNA that may influence human brain size and function via modulation of neocortical brain development.
Data availability
Small RNA-sequencing data and sample genotypes will be available via dbGaP with study accession number phs003106.v1.p1. Total RNA-sequencing data can be found under the dbGaP study phs001900.v1.p1. Scripts used to reproduce the analyses presented here are available via bitbucket code repository at https://bitbucket.org/steinlabunc/mirna-eqtl-manuscript/.
Article and author information
Author details
Funding
National Institutes of Health (R01MH120125,R01MH118349,U54EB020403,R00MH102357)
- Jason L Stein
National Institute of General Medical Sciences (5T32GM067553-13)
- Michael J Lafferty
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Human fetal brain tissue was obtained from the UCLA Gene and Cell Therapy Core following institutional review board regulations. This study was declared Exempt by the UNC Institutional Review Board (16-0054).
Copyright
© 2023, Lafferty et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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