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

By Gabriel Cuéllar-Partida, Joyce Y Tung, Nicholas Eriksson, Eva Albrecht, Fazil Aliev, Ole A. Andreassen, Inês Barroso, Jacques S Beckmann, Marco P. Boks, Cornelis J. Stam, Heather A. Boyd, Monique MB Breteler, Harry Campbell, Daniel I Chasman, Lynn F Cherkas, Gail Davies, Eco JC 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, Mohammad A 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. Pennix, 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, K. Stefansson, Nicholas J. Timpson, André G. Uitterlinden, Cornelia M. van Duijn, Frank JA 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 Magi, Ben M Neale, David M. Evans, Joseph K. Pickrell

Posted 07 Nov 2019
bioRxiv DOI: 10.1101/831321

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively 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 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

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