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

Robert Shore, Laura Covill, Kerry A. Pettigrew, William M. Brandler, Rebeca Diaz, Yiwang Xu, Javier A. Tello, Joel B. Talcott, Dianne F. Newbury, John Stein, Anthony P. Monaco, Silvia Paracchini*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1771-1779
Number of pages9
JournalHuman Molecular Genetics
Volume25
Issue number9
Early online date21 Feb 2016
DOIs
Publication statusPublished - 1 May 2016

Bibliographical note

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Funding: Royal Society (RG110387); University of St Andrews PhD scholarship; Wellcome Trust (090532/Z/09/Z); MRC (G0900747 91070); Wellcome Trust (097831/Z/11/Z an MRC Career Development Fellow - G1000569/1 and MR/J003719/1)

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