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

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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
Year: 2021
Journal: Translational psychiatry
PMID: 34330890
DOI: 10.1038/s41398-021-01480-x
PMCID: PMC8324785

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 (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. 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 (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs 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 [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 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.

#	Section	Preview
40	Discussion	We note that multivariate results should be interpreted with some caution. While combining data from…
41	Discussion	GWASs are increasingly successful in identifying genomic loci for complex human traits [48] and also…
42	Discussion	Despite our extensive effort, the first genome-wide significant SNP for childhood AGG has yet to be…
43	URLs	GWAS SOP: http://www.action-euproject.eu/content/data-protocols
44	URLs	MAGMA: https://ctg.cncr.nl/software/magma
45	URLs	SNPnexus: https://www.snp-nexus.org/index.html (Accessed 28 Aug 2019)
46	URLs	GWAS Catalog: https://www.ebi.ac.uk/gwas/ (Accessed 29 Aug 2019)
47	URLs	PhenoScanner: http://www.phenoscanner.medschl.cam.ac.uk/ (Accessed 29 Aug 2019)

Name	Type
1000 Genomes (Phase 3 Release 5) local	cohort
1000 Genomes Project	cohort
7-year olds local	cohort
ADHD	phenotype
adolescents	cohort
adult antisocial behavior	phenotype
adventurousness	phenotype
age at first birth	phenotype
age at smoking initiation	phenotype
AGGASEBA local	phenotype
AGG_Father local	phenotype
AGGM7 local	phenotype
AGG_Mother local	phenotype
AGGMother local	phenotype
AGGoverall local	cohort
AGGoverall local	phenotype
aggression	phenotype
Aggression (AGG) local	phenotype
Aggression (childhood) local	phenotype
AGGS13 local	phenotype
AGGSDQ local	phenotype
AGG_Self local	phenotype
AGGSelf local	phenotype
AGGSR local	phenotype
AGG_Teacher local	phenotype
AGGTeacher local	phenotype
anthropometric traits	phenotype
antisocial personality disorder	phenotype
anxiety	phenotype
ASD	phenotype
ASEBA scale local	phenotype
ASEBA scales local	phenotype
attention problems	phenotype
Australia	cohort
behavioral phenotypes	phenotype
birth weight	phenotype
cannabis dependence	phenotype
CD	phenotype
CD symptom score local	phenotype
childhood AGG local	phenotype
Childhood AGG polygenic score local	phenotype
childhood aggression local	phenotype
Childhood Aggression local	phenotype
childhood cohorts local	cohort
childhood IQ	phenotype
childhood traits local	phenotype
children	cohort
Children (7-year olds) local	cohort
cognition	phenotype
cognitive phenotypes	phenotype
cognitive traits	phenotype
college or university degree local	phenotype
complex traits	phenotype
conduct disorder	phenotype
Criminal convictions local	phenotype
CTI local	drug
developmental phenotypes local	phenotype
discovery GWAS	cohort
educational attainment	phenotype
educational outcomes	phenotype
European ancestry	cohort
externalizing disorders	phenotype
external phenotypes local	phenotype
External phenotypes local	phenotype
father-reported AGG local	phenotype
Father-reported AGG local	phenotype
GWAS	cohort
Having more children local	phenotype
Having offspring earlier in life local	phenotype
HDL cholesterol	phenotype
heart rate	phenotype
heart rate variability	phenotype
hyperactivity	phenotype
intelligence	phenotype
IPO13 local	gene
LDL local	drug
lifetime cannabis use local	drug
lipids	drug
MAGMA	drug
Mater-University of Queensland Study of Pregnancy local	cohort
mood disorders	phenotype
Mother-rated AGG local	phenotype
Neff local	drug
Netherlands Twin Register	cohort
neuroscientific phenotypes local	phenotype
New Zealand	cohort
oppositional defiant disorder	phenotype
parents	cohort
PCDH7 local	gene
personality traits	phenotype
PhenoScanner local	cohort
phenotype	phenotype
phenotypic correlation local	phenotype
polygenic risk score	cohort
psychiatric disorders	phenotype
psychiatric traits	phenotype
psychopathological phenotypes local	phenotype
QIMR	cohort
Queensland Institute for Medical Research local	cohort
reproductive traits	phenotype
Resting heart rate local	phenotype
rs11215217	variant
rs113599846 local	variant
rs13138213 local	variant
rs2485997 local	variant
rs2570485 local	variant
rs2764450	variant
rs3791116 local	variant
rs4714329 local	variant
sample overlap local	drug
sample size local	drug
schizophrenia	phenotype
SDQ local	phenotype
Self-rated AGG local	phenotype
self-reported AGG local	phenotype
Self-reported AGG local	phenotype
self-reported health	phenotype
smoking behavior	phenotype
smoking initiation	phenotype
smoking quantity	phenotype
SNP	cohort
Social dominance	phenotype
ST3GAL3	gene
study cohort	cohort
subjective well-being	phenotype
substance use	phenotype
Teacher-rated AGG local	phenotype
teacher-reported AGG local	phenotype
Teacher-reported AGG local	phenotype
teachers	cohort
testosterone	drug
Testosterone levels local	phenotype
TNRC18 local	gene
trait	phenotype
UKB	cohort
UK Biobank	cohort
USA	cohort

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