Genetic association study of childhood aggression across raters, instruments, and age
Authors: Ip Hill F. , van der Laan Camiel M. , Krapohl Eva M. L. , Brikell Isabell , Sánchez-Mora Cristina , Nolte Ilja M. , St Pourcain Beate , Bolhuis Koen , Palviainen Teemu , Zafarmand Hadi , Colodro-Conde Lucía , Gordon Scott , Zayats Tetyana , Aliev Fazil , Jiang Chang , Wang Carol A. , Saunders Gretchen , Karhunen Ville , Hammerschlag Anke R. , Adkins Daniel E. , Border Richard , Peterson Roseann E. , Prinz Joseph A. , Thiering Elisabeth , Seppälä Ilkka , Vilor-Tejedor Natàlia , Ahluwalia Tarunveer S. , Day Felix R. , Hottenga Jouke-Jan , Allegrini Andrea G. , Rimfeld Kaili , Chen Qi , Lu Yi , Martin Joanna , Soler Artigas María , Rovira Paula , Bosch Rosa , Español Gemma , Ramos Quiroga Josep Antoni , Neumann Alexander , Ensink Judith , Grasby Katrina , Morosoli José J. , Tong Xiaoran , Marrington Shelby , Middeldorp Christel , Scott James G. , Vinkhuyzen Anna , Shabalin Andrey A. , Corley Robin , Evans Luke M. , Sugden Karen , Alemany Silvia , Sass Lærke , Vinding Rebecca , Ruth Kate , Tyrrell Jess , Davies Gareth E. , Ehli Erik A. , Hagenbeek Fiona A. , De Zeeuw Eveline , Van Beijsterveldt Toos C.E.M. , Larsson Henrik , Snieder Harold , Verhulst Frank C. , Amin Najaf , Whipp Alyce M. , Korhonen Tellervo , Vuoksimaa Eero , Rose Richard J. , Uitterlinden André G. , Heath Andrew C. , Madden Pamela , Haavik Jan , Harris Jennifer R. , Helgeland Øyvind , Johansson Stefan , Knudsen Gun Peggy S. , Njolstad Pal Rasmus , Lu Qing , Rodriguez Alina , Henders Anjali K. , Mamun Abdullah , Najman Jackob M. , Brown Sandy , Hopfer Christian , Krauter Kenneth , Reynolds Chandra , Smolen Andrew , Stallings Michael , Wadsworth Sally , Wall Tamara L. , Silberg Judy L. , Miller Allison , Keltikangas-Järvinen Liisa , Hakulinen Christian , Pulkki-Råback Laura , Havdahl Alexandra , Magnus Per , Raitakari Olli T. , Perry John R. B. , Llop Sabrina , Lopez-Espinosa Maria-Jose , Bønnelykke Klaus , Bisgaard Hans , Sunyer Jordi , Lehtimäki Terho , Arseneault Louise , Standl Marie , Heinrich Joachim , Boden Joseph , Pearson John , Horwood L. John , Kennedy Martin , Poulton Richie , Eaves Lindon J. , Maes Hermine H. , Hewitt John , Copeland William E. , Costello Elizabeth J. , Williams Gail M. , Wray Naomi , Järvelin Marjo-Riitta , McGue Matt , Iacono William , Caspi Avshalom , Moffitt Terrie E. , Whitehouse Andrew , Pennell Craig E. , Klump Kelly L. , Burt S. Alexandra , Dick Danielle M. , Reichborn-Kjennerud Ted , Martin Nicholas G. , Medland Sarah E. , Vrijkotte Tanja , Kaprio Jaakko , Tiemeier Henning , Davey Smith George , Hartman Catharina A. , Oldehinkel Albertine J. , Casas Miquel , Ribasés Marta , Lichtenstein Paul , Lundström Sebastian , Plomin Robert , Bartels Meike , Nivard Michel G. , Boomsma Dorret I. 
Published: July 2021

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages 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 $$\left| {r_g} \right|$$

r

g

: 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 $$\left| {r_g} \right|$$

r

g

: 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.