Association of aggression with a novel microRNA binding site polymorphism in the wolframin gene

Rare mutations in the WFS1 gene lead to Wolfram syndrome, a severe multisystem disorder with progressive neurodegeneration and diabetes mellitus causing life-threatening complications and premature death. Only a few association studies using small clinical samples tested the possible effects of common WFS1 gene variants on mood disorders and suicide, the non-clinical spectrum has not been studied yet. Self-report data on Aggression, Impulsiveness, Anxiety, and Depression were collected from a large (N = 801) non-psychiatric sample. Single nucleotide polymorphisms (SNPs) were selected to provide an adequate coverage of the entire WFS1 gene, as well as to include putative microRNA binding site polymorphisms. Molecular analysis of the assumed microRNA binding site variant was performed by an in vitro reporter-gene assay of the cloned 3' untranslated region with coexpression of miR-668. Among the 17 WFS1 SNPs, only the rs1046322, a putative microRNA (miR-668) binding site polymorphism showed significant association with psychological dimensions after correction for multiple testing: those with the homozygous form of the minor allele reported higher aggression on the Buss-Perry Aggression Questionnaire (P = 0.0005). Functional effect of the same SNP was also demonstrated in a luciferase reporter system: the minor A allele showed lower repression compared to the major G allele, if co-expressed with miR-668. To our knowledge, this is the first report describing a microRNA binding site polymorphism of the WFS1 gene and its association with human aggression based on a large, non-clinical sample.