Genetic association study of childhood aggression across raters, instruments, and age

Author:

Ip Hill F.ORCID,van der Laan Camiel M.,Krapohl Eva M. L.,Brikell Isabell,Sánchez-Mora CristinaORCID,Nolte Ilja M.ORCID,St Pourcain BeateORCID,Bolhuis Koen,Palviainen TeemuORCID,Zafarmand Hadi,Colodro-Conde LucíaORCID,Gordon ScottORCID,Zayats Tetyana,Aliev FazilORCID,Jiang Chang,Wang Carol A.,Saunders Gretchen,Karhunen VilleORCID,Hammerschlag Anke R.,Adkins Daniel E.,Border RichardORCID,Peterson Roseann E.,Prinz Joseph A.,Thiering Elisabeth,Seppälä Ilkka,Vilor-Tejedor Natàlia,Ahluwalia Tarunveer S.ORCID,Day Felix R.ORCID,Hottenga Jouke-JanORCID,Allegrini Andrea G.,Rimfeld KailiORCID,Chen Qi,Lu YiORCID,Martin Joanna,Soler Artigas MaríaORCID,Rovira Paula,Bosch RosaORCID,Español Gemma,Ramos Quiroga Josep AntoniORCID,Neumann AlexanderORCID,Ensink Judith,Grasby KatrinaORCID,Morosoli José J.,Tong Xiaoran,Marrington Shelby,Middeldorp ChristelORCID,Scott James G.,Vinkhuyzen Anna,Shabalin Andrey A.,Corley Robin,Evans Luke M.ORCID,Sugden Karen,Alemany SilviaORCID,Sass LærkeORCID,Vinding Rebecca,Ruth KateORCID,Tyrrell Jess,Davies Gareth E.,Ehli Erik A.ORCID,Hagenbeek Fiona A.ORCID,De Zeeuw Eveline,Van Beijsterveldt Toos C.E.M.,Larsson Henrik,Snieder HaroldORCID,Verhulst Frank C.,Amin Najaf,Whipp Alyce M.,Korhonen Tellervo,Vuoksimaa Eero,Rose Richard J.,Uitterlinden André G.ORCID,Heath Andrew C.,Madden Pamela,Haavik JanORCID,Harris Jennifer R.,Helgeland Øyvind,Johansson StefanORCID,Knudsen Gun Peggy S.ORCID,Njolstad Pal RasmusORCID,Lu Qing,Rodriguez AlinaORCID,Henders Anjali K.,Mamun Abdullah,Najman Jackob M.,Brown SandyORCID,Hopfer Christian,Krauter Kenneth,Reynolds Chandra,Smolen Andrew,Stallings Michael,Wadsworth Sally,Wall Tamara L.,Silberg Judy L.,Miller AllisonORCID,Keltikangas-Järvinen LiisaORCID,Hakulinen Christian,Pulkki-Råback Laura,Havdahl AlexandraORCID,Magnus Per,Raitakari Olli T.,Perry John R. B.ORCID,Llop Sabrina,Lopez-Espinosa Maria-Jose,Bønnelykke Klaus,Bisgaard Hans,Sunyer Jordi,Lehtimäki TerhoORCID,Arseneault LouiseORCID,Standl Marie,Heinrich Joachim,Boden JosephORCID,Pearson JohnORCID,Horwood L. John,Kennedy MartinORCID,Poulton RichieORCID,Eaves Lindon J.,Maes Hermine H.,Hewitt John,Copeland William E.ORCID,Costello Elizabeth J.,Williams Gail M.,Wray NaomiORCID,Järvelin Marjo-RiittaORCID,McGue MattORCID,Iacono William,Caspi Avshalom,Moffitt Terrie E.,Whitehouse Andrew,Pennell Craig E.ORCID,Klump Kelly L.,Burt S. Alexandra,Dick Danielle M.ORCID,Reichborn-Kjennerud Ted,Martin Nicholas G.ORCID,Medland Sarah E.ORCID,Vrijkotte Tanja,Kaprio JaakkoORCID,Tiemeier HenningORCID,Davey Smith GeorgeORCID,Hartman Catharina A.,Oldehinkel Albertine J.ORCID,Casas Miquel,Ribasés MartaORCID,Lichtenstein PaulORCID,Lundström Sebastian,Plomin RobertORCID,Bartels MeikeORCID,Nivard Michel G.ORCID,Boomsma Dorret I.ORCID

Abstract

AbstractChildhood 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.

Publisher

Springer Science and Business Media LLC

Subject

Biological Psychiatry,Cellular and Molecular Neuroscience,Psychiatry and Mental health

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