title: The BDNF Val66Met variant affects gene expression through miR-146b.
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.
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
authors.forename: Pei-Ken
authors.initials: PK
authors.lastname: Hsu
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Mukai
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA. Electronic address: mk2758@columbia.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA; Department of Neuroscience, Columbia University, New York, NY, USA. Electronic address: jag90@columbia.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D056950:Period Circadian Proteins / Q000378:metabolism; D014633:Valine / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D053592:Interleukin-1 Receptor-Associated Kinases; D008715:Methionine; D035683:MicroRNAs; D056950:Period Circadian Proteins; D014633:Valine; C534190:Mirn146 microRNA, mouse; C533005:Npas4 protein, mouse; C539023:Per1 protein, mouse; C507769:Irak1 protein, mouse
keywords: BDNF; Knock-in mice; MicroRNA; Val66Met