Genome-wide association study identifies 48 common genetic variants associated with handedness
Cuellar-Partida, Gabriel; Tung, Joyce Y.; Eriksson, Nicholas; Albrecht, Eva; Aliev, Fazil; Andreassen, Ole A.; Barroso, Inês; Beckmann, Jacques S.; Boks, Marco P.; Boomsma, Dorret I.; Boyd, Heather A.; Breteler, Monique M.B.; Campbell, Harry; Chasman, Daniel I.; Cherkas, Lynn F.; Davies, Gail; de Geus, Eco J.C.; Deary, Ian J.; Deloukas, Panos; Dick, Danielle M.; Duffy, David L.; Eriksson, Johan G.; Esko, Tõnu; Feenstra, Bjarke; Geller, Frank; Gieger, Christian; Giegling, Ina; Gordon, Scott D.; Han, Jiali; Hansen, Thomas F.; Hartmann, Annette M.; Hayward, Caroline; Heikkilä, Kauko; Hicks, Andrew A.; Hirschhorn, Joel N.; Hottenga, Jouke Jan; Huffman, Jennifer E.; Hwang, Liang Dar; Ikram, M. Arfan; Kaprio, Jaakko; Kemp, John P.; Khaw, Kay Tee; Klopp, Norman; Konte, Bettina; Kutalik, Zoltan; Lahti, Jari; Li, Xin; Loos, Ruth J.F.; Luciano, Michelle; Ophoff, Roel A.
(2021) NATURE HUMAN BEHAVIOUR, volume 5, issue 1, pp. 59 - 70
(Article)
Abstract
Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10 -8) with left-handedness
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and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r G = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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Keywords: Experimental and Cognitive Psychology, Social Psychology, Behavioral Neuroscience, Journal Article
ISSN: 2397-3374
Publisher: Nature Publishing Group
Note: Funding Information: Professor John M. Starr and Professor Leena Peltonen have passed away. We have included them in memory of their work on this project. This research was conducted using the UK Biobank Resource (application number 12703). Access to the UK Biobank study data was funded by the University of Queensland (Early Career Researcher grant 2014002959 to N.W.). D.M.E. is funded by a National Health and Medical Research Council Senior Research Fellowship (APP1137714). G.C.-P. is funded by an Australia Research Council Discovery Early Career Researcher Award (DE180100976). C.M.L. is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). R.M. was supported by Estonian Research Council grant PUT PRG687 and institutional grant PP1GI19935 from Institute of Genomics, University of Tartu. M.I.M. funding support for this work comes from Wellcome (090532, 106130, 098381, 203141, 212259, 095101, 200837 and 099673/Z/12/Z) and the NIHR (NF-SI-0617-10090). N.W. is supported by an Australian National Health and Medical Research Council Early Career Fellowship (APP1104818). S.E.M. was funded by a NHMRC Senior Research Fellowship (APP1103623). I.B. is funded by Wellcome (WT206194). B.F. was supported by a grant from the Oak Foundation. We thank the research participants of 23andMe for making this study possible. Members of the 23andMe Research Team are as follows: M. Agee, A. Auton, R. K. Bell, K. Bryc, S. L. Elson, P. Fontanillas, N. A. Furlotte, B. Hicks, K. E. Huber, E. M. Jewett, Y. Jiang, A. Kleinman, K.-H. Lin, N. K. Litterman, M. H. McIntyre, K. F. McManus, J. L. Mountain, E. S. Noblin, C. A. M. Northover, S. J. Pitts, G. D. Poznik, J. F. Sathirapongsasuti, J. F. Shelton, S. Shringarpure, C. Tian, V. Vacic, X. Wang and C. H. Wilson. We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them and the entire ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome Trust (grant reference 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Netherlands Twin Register acknowledges funding from the Netherlands Organization for Scientific research (NWO), including NWO-Grant 480-15-001/674: Netherlands Twin Registry Repository and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI–NL, 184.021.007 and 184.033.111); the KNAW Academy Professor Award (PAH/6635 to D.I.B.); Amsterdam Public Health (APH) and Neuroscience Campus Amsterdam (NCA); the European Community 7th Framework Program (FP7/2007-2013): ENGAGE (HEALTH-F4-2007-201413) and ACTION (9602768). We also acknowledge The Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); the Collaborative Study of the Genetics of DZ twinning (NIH R01D0042157-01A1); the Developmental Study of Attention Problems in Young Twins (NIMH, RO1 MH58799-03); Major depression: stage 1 genome-wide association in population-based samples (MH081802); Determinants of Adolescent Exercise Behavior (NIDDK R01 DK092127-04); Grand Opportunity grants Integration of Genomics and Transcriptomics (NIMH 1RC2MH089951-01) and Developmental Trajectories of Psychopathology (NIMH 1RC2 MH089995); and the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA). The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (number 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project number 050-060-810. We thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera and M. Peters and C. Medina-Gomez for their help in creating the GWAS database, and K. Estrada, Y. Aulchenko and C. Medina-Gomez. for the creation and analyses of imputed data. We would like to thank K. Estrada, F. Rivadeneira, T. A. Knoch, M. Verkerk and A. Abuseiris. The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are very grateful to the study participants, the staff from the Rotterdam Study (particularly L. Buist and J. H. van den Boogert) and the participating general practitioners and pharmacists. We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study (HBCS). The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, the Folkhälsan Research Foundation, the Novo Nordisk Foundation, Finska Läkaresällskapet, the Juho Vainio Foundation, the Signe and Ane Gyllenberg Foundation, the University of Helsinki, the Ministry of Education, the Ahokas Foundation, and the Emil Aaltonen Foundation. In addition, we thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-up Study for their valuable contributions, and the Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School This work was supported in part by NIH R01 CA49449, P01 CA87969, UM1 CA186107 and UM1 CA167552. The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. We are very grateful to all DNBC families who took part in the study. We would also like to thank everyone involved in data collection and biological material handling. The DNBC was established based on a major grant from Danish National Research Foundation. Additional support for the DNBC was obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. The DNBC 7-year follow-up was supported by the Lundbeck Foundation (195/04) and the Danish Medical Research Council (SSVF 0646). The DNBC biobank is a part of the Danish National Biobank resource, which is supported by the Novo Nordisk Foundation. Phenotype and genotype data collection in the Finnish Twin Cohort has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE – European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose and AA15416 and K02AA018755 to D M Dick) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, and 312073 to J.K.). J.K. acknowledges support by the Academy of Finland (grants 265240, 263278). E.V. acknowledges support by the Academy of Finland (grant 314639). Finally, we thank the participants of all the cohorts for their valuable contribution. This publication is the work of the authors, and S.E.M. and D.M.E. will serve as guarantors for the contents of this paper. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: G.C.-P., N.E., D.A.H. and J.Y.T. are employees of 23andMe, Inc., and hold stock or stock options in 23andMe. S.H.M., K.S., H.S., S.S. and G.T. are employees of deCODE Genetics/Amgen. M.I.M. is a Wellcome Senior Investigator and a NIHR Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.I.M. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global; has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly; has stock options in Zoe Global; has received research funding from Abbvie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. As of June 2019, he is an employee of Genentech, and holder of Roche stock. All other authors report no conflicts of interest. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
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