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

By Hill F. Ip, Camiel M van der Laan, 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-Jan Hottenga, Andrea Allegrini, Eva M L Krapohl, 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, José J Morosoli, Xiaoran Tong, Shelby Marrington, Christel Middeldorp, James G Scott, Anna Vinkhuyzen, Andrey A. Shabalin, Robin Corley, Luke M. Evans, Karen Sugden, Silvia Alemany, Lærke Sass, Rebecca Vinding, Katherine S. Ruth, Jessica 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, Øyvind 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 RB Perry, Sabrina Llop, Maria-Jose Lopez-Espinosa, Klaus Bønnelykke, Hans Bisgaard, Jordi Sunyer, Terho Lehtimäki, Louise Arseneault, Marie Standl, Joachim Heinrich, Joseph Boden, John 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, Henning Tiemeier, George Davey Smith, Catharina A. Hartman, Albertine J. Oldehinkel, Miquel Casas, Marta Ribasés, Paul Lichtenstein, Sebastian Lundström, Robert Plomin, David Cesarini, Michel G Nivard, Dorret I Boomsma

Posted 29 Nov 2019
bioRxiv DOI: 10.1101/854927

Childhood aggressive behavior (AGG) has a substantial heritability, with limited success in genome-wide association studies. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across age from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data - i.e. within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE=0.0038). We found no genome-wide significant SNPs for AGGoverall. The 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 (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg=0.46 between self- and teacher-assessment to rg=0.81 between mother- and teacher-assessment. We obtained moderate to strong rgs 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 |rg |: 0.19 - 1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg=~ -0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg |: 0.46 - 0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater specific genetic etiology of AGG.

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