Abstract
We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 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.
Highlights
Handedness is one of the most researched human behavioural traits, yet one of the least understood
We recently identified the first statistically significant association with a handedness-related measure (PegQ) at the PCSK6 locus by screening cohorts of children selected for dyslexia [5,6]
We found no association for the variable number tandem repeat (VNTR), while the rs11855415 association with PegQ was confirmed in this subgroup (P = 4.8 × 10−4; Supplementary Material, Table S1)
Summary
Handedness is one of the most researched human behavioural traits, yet one of the least understood. The vast majority of people worldwide prefer using their right hand for writing and performing most tasks This observation implies a disadvantage for left-handedness and a large body of research has investigated whether being left-handed can increase susceptibility to particular traits or disorders [1]. While PCSK6 was the only gene that reached statistical significance, other genes and pathways involved in the determination of left–right structural asymmetries showed association with handedness both in the cohort selected for dyslexia and in the epidemiological cohort. The top associated gene in the general population cohort was located in proximity of GPC3 (P = 2.08×10−6) [6], a gene implicated in cardiac laterality defects [9] These data suggest that the same biological pathways controlling structural laterality may be partly implicated in contributing to behavioural laterality
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