Violent aggression predicted by multiple pre-adult environmental hits

Abstract

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention.

This work was supported by the Max Planck Society, the Max Planck Förderstiftung, the DFG (CNMPB), EXTRABRAIN EU-FP7, the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT), and EU-AIMS. The research of EUAIMS receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013), from the EFPIA companies, and from Autism Speaks. Moreover, support from Centro de Investigación en Red de Salud Mental (CIBERSAM); Instituto de Salud Carlos III (PI16/00998), Comissionat per a Universitats i Recerca del DIUE (2014SGR1636) and Spanish Ministry of Economy and Competitiveness (ES-EUEpiBrain, SAF2015-71526-REDT) is gratefully acknowledged. We thank all subjects for participating in the study, and all the many colleagues who have contributed over the past decade to the GRAS data collection.