Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.
Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 × 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR ≤ 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR ≤ 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom ; MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.
William M
WM
Brandler
Andrew P
AP
Morris
David M
DM
Evans
Thomas S
TS
Scerri
John P
JP
Kemp
Nicholas J
NJ
Timpson
Beate
B
St Pourcain
George Davey
GD
Smith
Susan M
SM
Ring
John
J
Stein
Anthony P
AP
Monaco
Joel B
JB
Talcott
Simon E
SE
Fisher
Caleb
C
Webber
Silvia
S
Paracchini
D000818:Animals; D019521:Body Patterning / Q000235:genetics; D001921:Brain / Q000503:physiopathology; D004410:Dyslexia / Q000235:genetics*; D007839:Functional Laterality / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D020412:Multifactorial Inheritance / Q000235:genetics*; D043484:Proprotein Convertases / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics
C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases