title: The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts.
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.
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY169TF, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Shore
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Covill
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY169TF, UK.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Pettigrew
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: William M
authors.initials: WM
authors.lastname: Brandler
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY169TF, UK.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Diaz
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY169TF, UK.
authors.forename: Yiwang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY169TF, UK.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Tello
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham, UK and.
authors.forename: Joel B
authors.initials: JB
authors.lastname: Talcott
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Dianne F
authors.initials: DF
authors.lastname: Newbury
authors.affiliation: Department of Physiology, Anatomy & Genetics, Parks Rd., Oxford OX1 3PT, UK.
authors.forename: John
authors.initials: J
authors.lastname: Stein
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Monaco
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY169TF, UK, sp58@st-andrews.ac.uk.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paracchini
mesh_terms: D007839:Functional Laterality / Q000235:genetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns / Q000235:genetics*; D018598:Minisatellite Repeats / Q000235:genetics*; D055457:Nodal Protein / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D043484:Proprotein Convertases / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D055457:Nodal Protein; D062085:RNA, Long Noncoding; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases