The BDNF Val66Met variant affects gene expression through miR-146b

Pei Ken Hsu, Bin Xu, Jun Mukai, Maria Karayiorgou*, Joseph A. Gogos

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Variation in gene expression is an important mechanism underlying susceptibility to complex disease and traits. Single nucleotide polymorphisms (SNPs) account for a substantial portion of the total detected genetic variation in gene expression but how exactly variants acting in trans modulate gene expression and disease susceptibility remains largely unknown. The BDNF Val66Met SNP has been associated with a number of psychiatric disorders such as depression, anxiety disorders, schizophrenia and related traits. Using global microRNA expression profiling in hippocampus of humanized BDNF Val66Met knock-in mice we showed that this variant results in dysregulation of at least one microRNA, which in turn affects downstream target genes. Specifically, we show that reduced levels of miR-146b (mir146b), lead to increased Per1 and Npas4 mRNA levels and increased Irak1 protein levels in vitro and are associated with similar changes in the hippocampus of hBDNFMet/Met mice. Our findings highlight trans effects of common variants on microRNA-mediated gene expression as an integral part of the genetic architecture of complex disorders and traits.

Original languageEnglish (US)
Pages (from-to)228-237
Number of pages10
JournalNeurobiology of Disease
Volume77
DOIs
StatePublished - May 1 2015

Keywords

  • BDNF
  • Knock-in mice
  • MicroRNA
  • Val66Met

ASJC Scopus subject areas

  • Neurology

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