MicroRNA-eQTLs in the developing human neocortex link miR-4707-3p expression to brain size

Michael J Lafferty; Nil Aygün; Niyanta K Patel; Oleh Krupa; Dan Liang; Justin M Wolter; Daniel H Geschwind; Luis de la Torre-Ubieta; Jason L Stein

doi:10.7554/eLife.79488

MicroRNA-eQTLs in the developing human neocortex link miR-4707-3p expression to brain size

Elife. 2023 Jan 11:12:e79488. doi: 10.7554/eLife.79488.

Authors

Michael J Lafferty^{1

2}, Nil Aygün^{1

2}, Niyanta K Patel^{1

2}, Oleh Krupa^{1

2}, Dan Liang^{1

2}, Justin M Wolter^{1

2

3

4}, Daniel H Geschwind^{5

6

7

8}, Luis de la Torre-Ubieta⁸, Jason L Stein^{1

2

4}

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States.
² UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States.
³ Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, United States.
⁴ Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, United States.
⁵ Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
⁶ Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
⁷ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
⁸ Department of Psychiatry and Biobehavioral Sciences, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.

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.

Keywords: eQTL; genetics; genomics; human; miRNA; neurogenesis; neuroscience.

MeSH terms

Gene Expression Profiling
Gene Expression Regulation
Humans
MicroRNAs* / genetics
MicroRNAs* / metabolism
Neocortex* / anatomy & histology
Neocortex* / growth & development
Neurogenesis*
Organ Size
Phenotype
Quantitative Trait Loci

MicroRNA-eQTLs in the developing human neocortex link miR-4707-3p expression to brain size

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