Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity, suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNA (miRNA) posttranscriptional gene regulators act by base-pairing to specific sequence sites, usually at the 3'UTR of the target mRNA. Variants at these sites might result in gene expression changes contributing to disease susceptibility. We investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by resequencing their 3'UTRs in patients with panic disorder (PD), obsessive-compulsive disorder (OCD), and in controls. We have found the C allele of rs28521337, located in a functional target site for miR-485-3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of OCD. We have also identified two new rare variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in one chromosome of a patient with PD. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two miRNAs, miR-509 and miR-128, the latter being a brain-enriched miRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the miRNA-mediated regulation of NTRK3, resulting in recovery of gene expression. These data implicate miRNAs as key posttranscriptional regulators of NTRK3 and provide a framework for allele-specific miRNA regulation of NTRK3 in anxiety disorders.

This work was supported by the “Instituto Carlos III and Fondo de Investigaciones Sanitarias” [CIBER-CB06/02/0058, CIBER-SAM, FIS/ISCIII:P1052565, ISCIII:GO3/184], the “Fundació la Marató-TV3” [014331], the “Departament d’Universitats Innovació i Empresa, Generalitat de Catalunya” [2005SGR00008] and the European Union Sixth Framework Programme Integrated Project SIROCCO [Grant LSHG-CT-2006-037900]. The Spanish National Genotyping Center (CeGen) is supported by “Genoma España” and the “Ministerio de Educación y Ciencia” (Spanish Government). M.M is a recipient of a FIS fellowship [FI05/0006]. Y.E was supported by the “Ramón y Cajal” Program [Spanish Ministry of Science and Education]. We would like to thank J.M. Mercader for his help in technical issues and suggestions as well as B. Cormand, A. Macaya, R. Corominas and E. Cuenca (Hospital Universitari Vall d'Hebron, Barcelona) for kindly proving us with control samples.