Abstract
Aggression and callous, uncaring, and unemotional (CU) traits are clinically related behavioral constructs caused by genetic and environmental factors. We performed polygenic risk score (PRS) analyses to investigate shared genetic etiology between aggression and these three CU-traits. Furthermore, we studied interactions of PRS with smoking during pregnancy and childhood life events in relation to CU-traits. Summary statistics for the base phenotype were derived from the EAGLE-consortium genome-wide association study of children’s aggressive behavior and were used to calculate individual-level genome-wide and gene-set PRS in the NeuroIMAGE target-sample. Target phenotypes were ‘callousness’, ‘uncaring’, and ‘unemotional’ sumscores of the Inventory of Callous-Unemotional traits. A total of 779 subjects and 1,192,414 single-nucleotide polymorphisms were available for PRS-analyses. Gene-sets comprised serotonergic, dopaminergic, glutamatergic, and neuroendocrine signaling pathways. Genome-wide PRS showed evidence of association with uncaring scores (explaining up to 1.59% of variance; self-contained Q = 0.0306, competitive-P = 0.0015). Dopaminergic, glutamatergic, and neuroendocrine PRS showed evidence of association with unemotional scores (explaining up to 1.33, 2.00, and 1.20% of variance respectively; self-contained Q-values 0.037, 0.0115, and 0.0473 respectively, competitive-P-values 0.0029, 0.0002, and 0.0045 respectively). Smoking during pregnancy related to callousness scores while childhood life events related to both callousness and unemotionality. Moreover, dopaminergic PRS appeared to interact with childhood life events in relation to unemotional scores. Our study provides evidence suggesting shared genetic etiology between aggressive behavior and uncaring, and unemotional CU-traits in children. Gene-set PRS confirmed involvement of shared glutamatergic, dopaminergic, and neuroendocrine genetic variation in aggression and CU-traits. Replication of current findings is needed.
| Original language | English |
|---|---|
| Pages (from-to) | 761-769 |
| Number of pages | 9 |
| Journal | Neuropsychopharmacology |
| Volume | 45 |
| Issue number | 5 |
| Early online date | 9 Jan 2020 |
| DOIs | |
| Publication status | Published - Apr 2020 |
Funding
This publication is the work of the authors and this research is supported by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 603016 (MATRICS) and no. 602805 (Aggressotype). The NeuroIMAGE-project was supported by NIH Grant R01MH62873 (to S.V.F.), NWO Large Investment Grant 1750102007010 and ZonMW Grant 60-60600-97-193 (to J.K.B.), and grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam. I.H.R., A.D., M.K., J.O. and P. J.H. reported no financial interests or potential conflicts of interest. J.K.B. has been a consultant to/advisory board member of/and/or a speaker for Janssen Cilag BV, Eli Lilly, Shire, Lundbeck, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. S.V.F. received income, potential income, travel expenses, continuing education support, and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, VAYA, Ironshore, Sunovion, Supernus, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD.
| Funders | Funder number |
|---|---|
| FP7/2007 | 602805 |
| S.V.F. | |
| National Institutes of Health | R01MH62873 |
| Seventh Framework Programme | 603016 |
| ZonMw | 60-60600-97-193 |
| Vrije Universiteit Amsterdam | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 1750102007010 |
| Seventh Framework Programme | |
| Universitair Medisch Centrum Groningen | |
| Radboud Universitair Medisch Centrum |
