Genome-wide association study identifies 48 common genetic variants associated with handedness

Gabriel Cuellar-Partida; Joyce Y Tung; Nicholas Eriksson; Eva Albrecht; Fazil Aliev; Ole A Andreassen; Inês Barroso; Jacques S Beckmann; Marco P Boks; Dorret I Boomsma; Heather A Boyd; Monique M B Breteler; Harry Campbell; Daniel I Chasman; Lynn F Cherkas; Gail Davies; Eco J C de Geus; Ian J Deary; Panos Deloukas; Danielle M Dick; David L Duffy; Johan G Eriksson; Tõnu Esko; Bjarke Feenstra; Frank Geller; Christian Gieger; Ina Giegling; Scott D Gordon; Jiali Han; Thomas F Hansen; Annette M Hartmann; Caroline Hayward; Kauko Heikkilä; Andrew A Hicks; Joel N Hirschhorn; Jouke-Jan Hottenga; Jennifer E Huffman; Liang-Dar Hwang; M Arfan Ikram; Jaakko Kaprio; John P Kemp; Kay-Tee Khaw; Norman Klopp; Bettina Konte; Zoltan Kutalik; Jari Lahti; Xin Li; Ruth J F Loos; Michelle Luciano; Sigurdur H Magnusson; Massimo Mangino; Pedro Marques-Vidal; Nicholas G Martin; Wendy L McArdle; Mark I McCarthy; Carolina Medina-Gomez; Mads Melbye; Scott A Melville; Andres Metspalu; Lili Milani; Vincent Mooser; Mari Nelis; Dale R Nyholt; Kevin S O'Connell; Roel A Ophoff; Cameron Palmer; Aarno Palotie; Teemu Palviainen; Guillaume Pare; Lavinia Paternoster; Leena Peltonen; Brenda W J H Penninx; Ozren Polasek; Peter P Pramstaller; Inga Prokopenko; Katri Raikkonen; Samuli Ripatti; Fernando Rivadeneira; Igor Rudan; Dan Rujescu; Johannes H Smit; George Davey Smith; Jordan W Smoller; Nicole Soranzo; Tim D Spector; Beate St Pourcain; John M Starr; Hreinn Stefánsson; Stacy Steinberg; Maris Teder-Laving; Gudmar Thorleifsson; Kári Stefánsson; Nicholas J Timpson; André G Uitterlinden; Cornelia M van Duijn; Frank J A van Rooij; Jaqueline M Vink; Peter Vollenweider; Eero Vuoksimaa; Gérard Waeber; Nicholas J Wareham; Nicole Warrington; Dawn Waterworth; Thomas Werge; H-Erich Wichmann; Elisabeth Widen; Gonneke Willemsen; Alan F Wright; Margaret J Wright; Mousheng Xu; Jing Hua Zhao; Peter Kraft; David A Hinds; Cecilia M Lindgren; Reedik Mägi; Benjamin M Neale; David M Evans; Sarah E Medland

doi:10.1038/s41562-020-00956-y

Genome-wide association study identifies 48 common genetic variants associated with handedness

Nat Hum Behav. 2021 Jan;5(1):59-70. doi: 10.1038/s41562-020-00956-y. Epub 2020 Sep 28.

Authors

Gabriel Cuellar-Partida^{1

2}, Joyce Y Tung², Nicholas Eriksson², Eva Albrecht³, Fazil Aliev^{4

5}, Ole A Andreassen^{6

7}, Inês Barroso^{8

9

10}, Jacques S Beckmann¹¹, Marco P Boks¹², Dorret I Boomsma^{13

14}, Heather A Boyd¹⁵, Monique M B Breteler¹⁶, Harry Campbell¹⁷, Daniel I Chasman^{18

19}, Lynn F Cherkas²⁰, Gail Davies^{21

22}, Eco J C de Geus^{13

14}, Ian J Deary^{21

22}, Panos Deloukas²³, Danielle M Dick^{4

24}, David L Duffy²⁵, Johan G Eriksson^{26

27

28

29}, Tõnu Esko^{30

31}, Bjarke Feenstra¹⁵, Frank Geller¹⁵, Christian Gieger^{32

33}, Ina Giegling³⁴, Scott D Gordon²⁵, Jiali Han^{35

36}, Thomas F Hansen^{37

38}, Annette M Hartmann³⁴, Caroline Hayward³⁹, Kauko Heikkilä⁴⁰, Andrew A Hicks⁴¹, Joel N Hirschhorn^{42

43

44}, Jouke-Jan Hottenga^{13

14}, Jennifer E Huffman³⁹, Liang-Dar Hwang¹, M Arfan Ikram⁴⁵, Jaakko Kaprio^{40

46}, John P Kemp^{1

47}, Kay-Tee Khaw⁴⁸, Norman Klopp⁴⁹, Bettina Konte³⁴, Zoltan Kutalik^{50

51}, Jari Lahti^{52

53

54}, Xin Li^{35

36}, Ruth J F Loos^{9

55

56}, Michelle Luciano^{21

22}, Sigurdur H Magnusson⁵⁷, Massimo Mangino²⁰, Pedro Marques-Vidal⁵⁸, Nicholas G Martin²⁵, Wendy L McArdle⁵⁹, Mark I McCarthy^{60

61

62

63}, Carolina Medina-Gomez^{45

64}, Mads Melbye^{15

65

66}, Scott A Melville⁴¹, Andres Metspalu³⁰, Lili Milani³⁰, Vincent Mooser⁶⁷, Mari Nelis³⁰, Dale R Nyholt^{25

68}, Kevin S O'Connell⁶, Roel A Ophoff^{69

70

71}, Cameron Palmer⁷², Aarno Palotie⁴⁰, Teemu Palviainen⁴⁰, Guillaume Pare⁷³, Lavinia Paternoster⁷⁴, Leena Peltonen⁷⁵, Brenda W J H Penninx^{14

76}, Ozren Polasek^{77

78}, Peter P Pramstaller⁴¹, Inga Prokopenko^{79

80}, Katri Raikkonen⁵², Samuli Ripatti⁴⁰, Fernando Rivadeneira^{45

64}, Igor Rudan⁸¹, Dan Rujescu³⁴, Johannes H Smit^{14

76}, George Davey Smith⁷⁴, Jordan W Smoller^{82

83}, Nicole Soranzo⁸, Tim D Spector²⁰, Beate St Pourcain^{74

84

85}, John M Starr^{86

87}, Hreinn Stefánsson⁵⁷, Stacy Steinberg⁵⁷, Maris Teder-Laving³⁰, Gudmar Thorleifsson⁵⁷, Kári Stefánsson⁵⁷, Nicholas J Timpson⁷⁴, André G Uitterlinden^{45

64}, Cornelia M van Duijn^{45

64}, Frank J A van Rooij⁴⁵, Jaqueline M Vink^{13

88}, Peter Vollenweider⁵⁸, Eero Vuoksimaa⁴⁰, Gérard Waeber⁵⁸, Nicholas J Wareham⁹, Nicole Warrington¹, Dawn Waterworth⁸⁹, Thomas Werge^{37

65

90}, H-Erich Wichmann⁹¹, Elisabeth Widen⁴⁰, Gonneke Willemsen¹³, Alan F Wright³⁹, Margaret J Wright^{92

93}, Mousheng Xu⁹⁴, Jing Hua Zhao⁹⁵, Peter Kraft⁹⁴, David A Hinds², Cecilia M Lindgren^{60

96}, Reedik Mägi³⁰, Benjamin M Neale^{31

97}, David M Evans^{98

99}, Sarah E Medland^{100

101}

Affiliations

¹ The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia.
² 23andMe, Inc., Sunnyvale, CA, USA.
³ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁴ Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
⁵ Karabuk University, Faculty of Business, Karabük, Turkey.
⁶ NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁸ Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
⁹ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
¹⁰ Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
¹¹ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
¹² Department of Psychiatry, UMC Utrecht Brain Center, University Utrecht, Utrecht, The Netherlands.
¹³ Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
¹⁴ Amsterdam Public Health research institute, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
¹⁵ Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
¹⁶ Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹⁷ Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
¹⁸ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁹ Harvard Medical School, Boston, MA, USA.
²⁰ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
²¹ Department of Psychology, University of Edinburgh, Edinburgh, UK.
²² Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
²³ William Harvey Research Institute, Barts and the London Medical School, and the Centre for Genomic Health, Queen Mary University of London, London, UK.
²⁴ Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
²⁵ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²⁶ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
²⁷ Folkhälsan Research Center, Helsinki, Finland.
²⁸ Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore, Singapore.
²⁹ Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³⁰ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
³¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³² Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
³³ German Center for Diabetes Research (DZD), München-Neuherberg, Neuherberg, Germany.
³⁴ University Clinic and Outpatient Clinic for Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
³⁵ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
³⁶ Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
³⁷ Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.
³⁸ Danish Headache Center, Copenhagen University Hospital, Glostrup, Denmark.
³⁹ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁴⁰ Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
⁴¹ Institute for Biomedicine, Eurac Research, Bolzano, Italy.
⁴² Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.
⁴³ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁴⁴ Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁴⁵ Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
⁴⁶ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁴⁷ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁴⁸ Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴⁹ Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
⁵⁰ Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland.
⁵¹ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁵² Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
⁵³ Turku Institute for Advanced Studies, University of Turku, Turku, Finland.
⁵⁴ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁵⁵ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁶ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁷ deCODE Genetics, Reykjavik, Iceland.
⁵⁸ Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁵⁹ Bristol Medical School, University of Bristol, Bristol, UK.
⁶⁰ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁶¹ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
⁶² Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
⁶³ Human Genetics, Genentech, South San Francisco, CA, USA.
⁶⁴ Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
⁶⁵ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁶⁶ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁶⁷ Service of Clinical Chemistry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁶⁸ School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
⁶⁹ Department of Human Genetics, University California Los Angeles, Los Angeles, CA, USA.
⁷⁰ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA.
⁷¹ Department of Psychiatry, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁷² Department of Computer Science, Columbia University, New York, NY, USA.
⁷³ Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
⁷⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁷⁵ Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
⁷⁶ Department of Psychiatry, Amsterdam UMC, VU University, Amsterdam, The Netherlands.
⁷⁷ Department of Public Health, University of Split School of Medicine, Split, Croatia.
⁷⁸ Research Unit, Psychiatric Hospital Sveti Ivan, Zagreb, Croatia.
⁷⁹ Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford, UK.
⁸⁰ Section of Genomics of Common Disease, Department of Medicine, Imperial College London, London, UK.
⁸¹ Centre for Global Health Research, The Usher Institute, University of Edinburgh, Edinburgh, UK.
⁸² Department of Psychiatry and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸³ Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
⁸⁴ Max Planck Institute for Psycholinguistics, Wundtlaan, Nijmegen, The Netherlands.
⁸⁵ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
⁸⁶ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
⁸⁷ Centre for Cognitive Ageing and Cognitive Epidemilogy, University of Edinburgh, Edinburgh, UK.
⁸⁸ Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands.
⁸⁹ Human Genetics, GlaxoSmithKline, Collegeville, PA, USA.
⁹⁰ The Lundbeck Foundation's IPSYCH Initiative, Copenhagen, Denmark.
⁹¹ Institute of Epidemiology, Helmholtz Center, Munich, Germany.
⁹² Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
⁹³ Centre for Advanced Imaging, The University of Queensland, Brisbane, Queensland, Australia.
⁹⁴ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, MA, USA.
⁹⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁹⁶ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
⁹⁷ Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹⁸ The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia. d.evans1@uq.edu.au.
⁹⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. d.evans1@uq.edu.au.
¹⁰⁰ The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia. Sarah.Medland@qimrberghofer.edu.au.
¹⁰¹ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Sarah.Medland@qimrberghofer.edu.au.

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 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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Female
Functional Laterality / genetics*
Gene Frequency / genetics
Genetic Loci / genetics
Genetic Variation / genetics*
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Male
Middle Aged
Polymorphism, Single Nucleotide / genetics
Quantitative Trait, Heritable
Sex Factors

Abstract

Publication types

MeSH terms

Grants and funding