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

Neurobiol Dis. 2015 May:77:228-37. doi: 10.1016/j.nbd.2015.03.004. Epub 2015 Mar 11.

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 hBDNF(Met/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.

Keywords: BDNF; Knock-in mice; MicroRNA; Val66Met.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain-Derived Neurotrophic Factor / genetics*
  • Gene Expression Regulation / genetics*
  • Hippocampus / metabolism
  • Humans
  • In Vitro Techniques
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Methionine / genetics*
  • Mice
  • Mice, Transgenic
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Period Circadian Proteins / metabolism
  • Valine / genetics*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Brain-Derived Neurotrophic Factor
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • Npas4 protein, mouse
  • Per1 protein, mouse
  • Period Circadian Proteins
  • Methionine
  • Interleukin-1 Receptor-Associated Kinases
  • Irak1 protein, mouse
  • Valine

Associated data

  • GENBANK/GSE44817