• restless legs syndrome;
  • depression;
  • miR-330;
  • MEK5;
  • GWAS

Functional variants that contribute to genomewide association study (GWAS) signals are difficult to identify. MicroRNAs could contribute to some of these gene–trait relationships. We compiled a set of GWAS trait gene SNPs that were predicted to affect microRNA regulation of mRNA. Trait associations were tested in a sample of 6725 European-American (EA) and African-American (AA) subjects that were interviewed using the polydiagnostic SSADDA to diagnose major psychiatric disorders. A predicted miR-330-3p target site SNP (rs41305272) in mitogen-activated protein kinase kinase 5 (MAP2K5) mRNA was in LD (d′ = 1.0, r2 = 0.02) with a reported GWAS-identified variant for restless legs syndrome (RLS), a disorder frequently comorbid with anxiety and depression, possibly because of a shared pathophysiology. We examined the SNP's association with mood and anxiety-related disorders. Rs41305272 was associated with agoraphobia (Ag) in EAs (odds ratio [OR] = 1.95, P = 0.007; 195 cases) and AAs (OR = 3.2, P = 0.03; 148 cases) and major depressive disorder (MDD) in AAs (OR = 2.64, P = 0.01; 427 cases), but not EAs (465 cases). Rs41305272*T carrier frequency was correlated with the number of anxiety and depressive disorders diagnosed per subject. RLS was not evaluated in our subjects. Predicted miR-330-3p target genes were enriched in pathways relevant to psychiatric disorders. These findings suggest that microRNA target site information may be useful in the analysis of GWAS signals for complex traits. MiR-330-3p and MAP2K5 are potentially important contributors to mood and anxiety-related traits. With support from additional studies, these findings could add to the large number of risk genes identified through association to medical disorders that have primary psychiatric effects. © 2014 Wiley Periodicals, Inc.