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Genetic Association Study of Childhood Aggression across raters, instruments and age

By Hill F. Ip, Camiel M van der Laan, Eva M L Krapohl, Isabell Brikell, Cristina Sánchez-Mora, Ilja M. Nolte, Beate St Pourcain, Koen Bolhuis, Teemu Palviainen, Hadi Zafarmand, Lucía Colodro-Conde, Scott Gordon, Tetyana Zayats, Fazil Aliev, Chang Jiang, Carol A Wang, Gretchen Saunders, Ville Karhunen, Anke R Hammerschlag, Daniel E Adkins, Richard Border, Roseann E Peterson, Joseph A Prinz, Elisabeth Thiering, Ilkka Seppälä, Natàlia Vilor-Tejedor, Tarunveer S Ahluwalia, Felix R Day, Jouke J Hottenga, Andrea G. Allegrini, Kaili Rimfeld, Qi Chen, Yi Lu, Joanna Martin, María Soler Artigas, Paula Rovira, Rosa Bosch, Gemma Español, Josep Antoni Ramos Quiroga, Alexander Neumann, Judith Ensink, Katrina Grasby, Jose J. Morosoli, Xiaoran Tong, Shelby Marrington, Christel Middeldorp, James G Scott, Anna Vinkhuyzen, Andrey Shabalin, Robin Corley, Luke M. Evans, Karen Sugden, Silvia Alemany, Lærke Sass, Rebecca Vinding, Katherine S Ruth, Jess Tyrrell, Gareth E. Davies, Erik A Ehli, Fiona A. Hagenbeek, Eveline De Zeeuw, Toos C.E.M. Van Beijsterveldt, Henrik Larsson, Harold Snieder, Frank C Verhulst, Najaf Amin, Alyce M Whipp, Tellervo Korhonen, Eero Vuoksimaa, Richard J Rose, André G. Uitterlinden, Andrew C. Heath, Pamela Madden, Jan Haavik, Jennifer R Harris, Oyvind Helgeland, Stefan Johansson, Gun Peggy S Knudsen, Pal Rasmus Njolstad, Qing Lu, Alina Rodriguez, Anjali K. Henders, Abdullah Mamun, Jackob M Najman, Sandy Brown, Christian Hopfer, Kenneth Krauter, Chandra Reynolds, Andrew Smolen, Michael Stallings, Sally Wadsworth, Tamara Wall, Judy L Silberg, Allison Miller, Liisa Keltikangas-Järvinen, Christian Hakulinen, Laura Pulkki-Råback, Alexandra Havdahl, Per Magnus, Olli T Raitakari, John R B Perry, Sabrina Llop, Maria-Jose Lopez-Espinosa, Klaus Bønnelykke, Hans Bisgaard, Jordi Sunyer, Terho Lehtimaki, Louise Arseneault, Marie Standl, Joachim Heinrich, Joseph Boden, John M Pearson, John Horwood, Martin A Kennedy, Richie Poulton, Lindon J. Eaves, Hermine H Maes, John Hewitt, William E. Copeland, Elizabeth J Costello, Gail M Williams, Naomi R. Wray, Marjo-Riitta Järvelin, Matt McGue, William Iacono, Avshalom Caspi, Terrie E. Moffitt, Andrew Whitehouse, Craig E. Pennell, Kelly L Klump, S Alexandra Burt, Danielle M. Dick, Ted Reichborn-Kjennerud, Nicholas G Martin, Sarah E Medland, Tanja Vrijkotte, Jaakko Kaprio, Lorenza Dall'Aglio, George Davey Smith, Catharina A. Hartman, Albertine J. Oldehinkel, Miquel Casas, Marta Ribasés, Paul Lichtenstein, Sebastian Lundstrom, Robert Plomin, Meike Bartels, Michel G. Nivard, Dorret I Boomsma

Posted 29 Nov 2019
bioRxiv DOI: 10.1101/854927

Background: Human aggressive behavior (AGG) has a substantial genetic component. Here we present a large genome-wide association meta-analysis (GWAMA) of childhood AGG. Methods: We analyzed assessments of AGG for a total of 328,935 observations from 87,485 children (aged 1.5 - 18 years), from multiple assessors, instruments, and ages, while accounting for sample overlap. We performed an overall analysis and meta-analyzed subsets of the data within rater, instrument, and age. Results: Heritability based on the overall meta-analysis (AGGall) that could be attributed to Single Nucleotide Polymorphisms (SNPs) was 3.31% (SE=0.0038). No single SNP reached genome-wide significance, but gene-based analysis returned three significant genes: ST3GAL3 (P=1.6E-06), PCDH7 (P=2.0E-06) and IPO13 (P=2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children and in retrospectively assessed childhood aggression. We obtained moderate-to-strong genetic correlations (r\_g's) with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range.|r\_g |:.0.19 - 1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r\_g=~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range.|r\_g |:.0.46 - 0.60). Genetic correlations between AGG and psychiatric disorders were strongest for mother- and self-reported AGG. Conclusions: The current GWAMA of childhood aggression provides a powerful tool to interrogate the genetic etiology of AGG by creating individual polygenic scores and genetic correlations with psychiatric traits. ### Competing Interest Statement Miquel Casas has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire and Lundbeck and served as consultant for Eli Lilly and Co., Janssen-Cilag, Shire and Lundbeck. Josep Antoni Ramos Quiroga was on the speakers’ bureau and/or acted as consultant Eli-Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medicine, Exeltis and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Medice and Eli-Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió.

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