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Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill

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Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill William M. Brandler1,2, Andrew P. Morris1, David M. Evans3,4, Thomas S. Scerri5, John P. Kemp3,4, Nicholas J. Timpson3,4, Beate St Pourcain4, George Davey Smith3,4, Susan M. Ring3, John Stein6, Anthony P. Monaco1, Joel B. Talcott7, Simon E. Fisher8,9, Caleb Webber2*, Silvia Paracchini10* 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 2 MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom, 3 MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom, 4 School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom, 5 The Walter and Eliza Hall Research Institute of Medical Research, Melbourne, Australia, 6 Department of Physiology, University of Oxford, Oxford, United Kingdom, 7 School of Life and Health Sciences, Aston University, Birmingham, United Kingdom, 8 Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands, 9 Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands, 10 School of Medicine, University of St Andrews, St Andrews, United Kingdom Abstract 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 = 8.6861029), 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. Citation: Brandler WM, Morris AP, Evans DM, Scerri TS, Kemp JP, et al. (2013) Common Variants in Left/Right Asymmetry Genes and Pathways Are Associated with Relative Hand Skill. PLoS Genet 9(9): e1003751. doi:10.1371/journal.pgen.1003751 Editor: Daniel H. Geschwind, University of California Los Angeles, United States of America Received March 7, 2013; Accepted July 10, 2013; Published September 12, 2013 Copyright: ß 2013 Brandler et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the University of St Andrews, the UK Medical Research Council (grant number G0800523/86473 to SP), the Max Plank Society, and the the EU (Neurodys, 018696). Genotyping at the Wellcome Trust Centre for Human Genetics was supported by the Wellcome Trust (090532/Z/09/Z) and a Medical Research Council Hub Grant (G0900747 91070). Core support for ALSPAC was provided by the UK Medical Research Council and the Wellcome Trust (092731) and the University of Bristol. SP is a Royal Society University Research Fellow. CW is also funded by the UK Medical Research Funding and the EU (GENCODYS, 241995). APMor was supported by the Wellcome Trust (grant numbers WT075491, WT090532, and WT098017). WMB is the recipient of a Nuffield Department of Medicine Prize Studentship. JPK is funded by a Wellcome Trust PhD studentship (WT083431MA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] (CW); [email protected] (SP) Introduction of strong left-handers, show left-hemisphere dominance for language [14]. Because language, like handedness, evolved Humans display such striking cerebral asymmetries that we primarily along the human lineage, it has been proposed that have been labeled, ‘‘The Lopsided Ape’’ [1]. The prevalence of the two evolved together [15]. It has also been hypothesized that right-handedness for tool use in excess of 85% across all human atypical cerebral asymmetries are associated with neurodevelop- societies implies left-hemisphere dominance for controlling hand mental disorders. Although many associations appear to be preference [2,3]. The same degree of collective population bias is spurious [16], dyslexia has been associated with structural and not observed in the other great apes [4,5], suggesting right- functional asymmetry differences, particularly in language related handedness evolved along the human lineage [6]. Studies of fossil regions like the superior temporal gyrus (which includes the hominins suggest that the evolution of right-handedness dates back planum temporale) [17,18]. Schizophrenia has been associated over half a million years [7], and is shared with Homo with both reduced planum temporale asymmetry [19–21] and an neanderthalensis [8,9] and Homo heidelbergensis [10]. increased prevalence of left-handedness [22]. Handedness correlates with asymmetries of both the motor Both cerebral asymmetry and handedness are heritable traits, cortex and language-related areas of the brain, such as the planum with additive genetic effects estimated to account for about a half temporale [11–13]. Furthermore, there is a weak correlation and a quarter of the variance, respectively [23–25]. Heritability between language lateralization and handedness: in a study of 326 estimates are consistent with theories that propose a single causal individuals, 96% of strong right-handers, as compared with 73% gene underlies handedness [26–28], however population genomics PLOS Genetics | www.plosgenetics.org 1 September 2013 | Volume 9 | Issue 9 | e1003751 Genetics of Handedness Author Summary identified a variable number tandem repeat (VNTR), close to rs11855415, associated with degree of handedness, providing Humans have developed a population level bias towards further evidence that PCSK6 is important in the development of right-handedness for tool-use. Understanding the genetic handedness [41]. basis of handedness can help explain why this bias exists Here we have genotyped the replication cohorts from our and may offer clues into the evolution of handedness and original study genome-wide, and perform a meta-analysis after brain asymmetry. We have tested for correlation between imputation with reference panels from the 1000 Genomes Project relative hand skill and hundreds of thousands of genetic [42]. The PCSK6 locus is the only genome-wide significant signal variants in a cohort of individuals with reading disability. observed. Because PCSK6 plays a key role in regulating the The strongest associated variant is in the gene PCSK6,an activity of NODAL during the development of LR asymmetry in enzyme that cleaves NODAL into an active form. NODAL vertebrates [40], we hypothesize that other genes in this pathway plays a key role during the establishment of left/right (LR) asymmetry in diverse species, from snails to mammals. are relevant for the development of handedness. Performing gene- Pcsk6 knock-out mice display LR asymmetry defects like set enrichment analysis, we identify an over-representation of heterotaxia (abnormal organ positioning). We uncovered SNPs strongly associated with relative hand skill in the human further variants associated with relative hand skill in the orthologs of genes that cause asymmetry defects when disrupted in human versions of genes that also cause the LR asymmetry mice. We replicate these results in a large independent general phenotypes heterotaxia, and situs inversus (reversal of population cohort without reading disability. Our results suggest organ asymmetry) when knocked out in mice. These that handedness is a complex trait controlled in part by genes results replicate in an independent general population responsible for the establishment of LR body asymmetry early in cohort without reading disability. We propose that development. handedness is under the control of many variants, some of which are in genes that also contribute to the Results determination of body LR asymmetry. The study participants are derived from four cohorts (Table 1), three with RD (cohorts 1–3, n = 185, 374, and 169 respectively), theory predicts that a significant proportion of the genetic variance and a general population cohort (cohort 4, n = 2,666). The samples in common traits is the results of multiple common variants of from cohorts 1 and 2 were selected as part of an ongoing study of small effect [29–31]. Indeed, the first direct molecular studies of dyslexia [43,44]. The samples from cohorts 3 and 4 are part of the handedness support the view that it has
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