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We recently reported the association of the  PCSK6  gene with handedness through a quantitative genome-wide association study (GWAS;  P  &lt; 0.5 × 10 −8 ) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left–right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same  PCSK6  locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the  PCSK6  locus combining further genetic analysis,  in silico  predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short  PCSK6  isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.

The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts