Genetic association study of childhood aggression across raters, instruments, and age
Ip HF., van der Laan CM., Krapohl EML., Brikell I., Sánchez-Mora C., Nolte IM., St Pourcain B., Bolhuis K., Palviainen T., Zafarmand H., Colodro-Conde L., Gordon S., Zayats T., Aliev F., Jiang C., Wang CA., Saunders G., Karhunen V., Hammerschlag AR., Adkins DE., Border R., Peterson RE., Prinz JA., Thiering E., Seppälä I., Vilor-Tejedor N., Ahluwalia TS., Day FR., Hottenga JJ., Allegrini AG., Rimfeld K., Chen Q., Lu Y., Martin J., Soler Artigas M., Rovira P., Bosch R., Español G., Ramos Quiroga JA., Neumann A., Ensink J., Grasby K., Morosoli JJ., Tong X., Marrington S., Middeldorp C., Scott JG., Vinkhuyzen A., Shabalin AA., Corley R., Evans LM., Sugden K., Alemany S., Sass L., Vinding R., Ruth K., Tyrrell J., Davies GE., Ehli EA., Hagenbeek FA., De Zeeuw E., Van Beijsterveldt TCEM., Larsson H., Snieder H., Verhulst FC., Amin N., Whipp AM., Korhonen T., Vuoksimaa E., Rose RJ., Uitterlinden AG., Heath AC., Madden P., Haavik J., Harris JR., Helgeland Ø., Johansson S., Knudsen GPS., Njolstad PR., Lu Q., Rodriguez A., Henders AK., Mamun A., Najman JM., Brown S., Hopfer C., Krauter K., Reynolds C., Smolen A., Stallings M., Wadsworth S., Wall TL., Silberg JL., Miller A., Keltikangas-Järvinen L., Hakulinen C., Pulkki-Råback L., Havdahl A., Magnus P., Raitakari OT.
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 ∣ 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.