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Leveraging aggression risk gene expression in the developing and adult human brain to guide future precision interventions

Molecular Psychiatry volume 26, pages 2680–2682 (2021)Cite this article

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Pathological aggressive behavior occurs in both clinical and non-clinical populations across the lifespan, with considerable prevalence in people with neurodevelopmental disorders (NDDs), including autism spectrum disorder [1] and attention-deficit/hyperactivity disorder [2]. Aggression significantly interferes with educational and social functioning, with negative interpersonal consequences far beyond childhood. Thus, an aspirational goal in caring for people with significant NDDs is risk stratification, mitigation, and prevention of aggressive behavior. Enhanced understanding of the genetic landscape contributing specifically to aggressive behavior in humans, and the possible existence of critical periods during which intervention may be most impactful will facilitate these goals. We thus read with interest a recent study from Zhang-James et al. in Molecular Psychiatry identifying 40 genes likely to play an important role in regulation of human aggression, synthesized from human genome-wide association studies (GWAS), rodent transcriptomic studies, and single-gene human disorders or knockout mouse studies [3]. These aggression risk genes (ARGs) were interconnected by functional network analysis, with multiple networks relevant to nervous system development. However, whether ARG expression is enriched in specific human brain regions during development or adulthood, or whether ARG expression in individual brain regions is distinctly regulated during development, is unknown. Such findings might further validate the ARGs as delineated by Zhang-James et al., support the relevance of transcriptomic mechanisms for aggression, and narrow potential brain regions and time periods as interventional targets for aggression in children and adults.

Our findings from these two complementary analyses of BrainSpan extend the findings from Zhang-James et al., suggesting that not only do ARGs participate in functional networks relevant to the nervous system, but also demonstrate transcriptional enrichment and unique developmental regulation within distinct brain regions. Because BrainSpan encompasses neurotypical individuals, it is possible that our findings may differ were our transcriptional reference to include individuals with NDDs. However, similar to our study, previous studies have mapped ASD-risk genes onto specific brain regions, cell types, and developmental time points using BrainSpan [7]. Encouragingly, most of the brain regions identified by our analysis, especially frontal, prefrontal, and primary sensory cortices, as well as the amygdala, have been strongly implicated in aggression regulation in clinical NDD populations, including ASD [8], and schizophrenia [9]. Interestingly, there is mounting evidence supporting a role for the cerebellum in social behavior, including a recent study of bidirectional aggression modulation by Purkinje neurons in the cerebellar vermis [10]. Future cell-specific investigations from human brain or animal models will likely be useful in further narrowing to identify subregions and individual cell types relevant for aggression. Taken together, we believe this work illustrates a cause for optimism in future translational aggression studies that build upon convergent layers of evidence to explore increasingly precise interventions acting on distinct brain regions during key developmental timepoints, with a long-term goal to improve outcomes in clinical populations.

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Fig. 1: Aggression risk gene brain region enrichment and developmental regulation.

References

  1. Kanne SM, Mazurek MO. Aggression in children and adolescents with ASD: prevalence and risk factors. J Autism Dev Disord. 2011;41:926–37.

    Article  Google Scholar 

  2. Saylor KE, Amann BH. Impulsive aggression as a comorbidity of attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol. 2016;26:19–25.

    Article  Google Scholar 

  3. Zhang-James Y, Fernàndez-Castillo N, Hess JL, Malki K, Glatt SJ, Cormand B, et al. An integrated analysis of genes and functional pathways for aggression in human and rodent models. Mol Psychiatry. 2019;24:1655–67. https://doi.org/10.1038/s41380-018-0068-7.

    Article  CAS  PubMed  Google Scholar 

  4. Miller JA, Ding SL, Sunkin SM, Smith KA, Ng L, Szafer A, et al. Transcriptional landscape of the prenatal human brain. Nature. 2014;508:199–206.

    Article  CAS  Google Scholar 

  5. Dougherty JD, Schmidt EF, Nakajima M, Heintz N. Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells. Nucleic Acids Res. 2010;38:4218–30.

    Article  CAS  Google Scholar 

  6. Specific Expression Analysis (SEA). http://genetics.wustl.edu/jdlab/csea-tool-2/. Accessed 4 July 2020.

  7. Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT, Muhle RA, et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell. 2013;155:997–1007.

    Article  CAS  Google Scholar 

  8. Ibrahim K, Eilbott JA, Ventola P, He G, Pelphrey KA, McCarthy G, et al. Reduced amygdala-prefrontal functional connectivity in children with autism spectrum disorder and co-occurring disruptive behavior. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019;4:1031–41.

    PubMed  PubMed Central  Google Scholar 

  9. Hoptman MJ. Impulsivity and aggression in schizophrenia: a neural circuitry perspective with implications for treatment. CNS Spectr. 2015;20:280–6.

    Article  Google Scholar 

  10. Jackman SL, Chen CH, Offermann HL, Drew IR, Harrison BM, Bowman AM, et al. Cerebellar Purkinje cell activity modulates aggressive behavior. Elife. 2020;9:e53229.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grants K23MH116339 (ASL) and R01MH114927 (TVF).

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Authors and Affiliations

  1. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37212, USA

    Ahra Kim & Simon N. Vandekar

  2. Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, 37212, USA

    Sarah L. Rader & Alan S. Lewis

  3. Yale Child Study Center, Yale School of Medicine, New Haven, CT, 06520, USA

    Thomas V. Fernandez

  4. Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, 37212, USA

    Alan S. Lewis

  5. Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, 37212, USA

    Alan S. Lewis

  6. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA

    Alan S. Lewis

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  1. Ahra Kim
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Correspondence to Alan S. Lewis.

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Kim, A., Rader, S.L., Fernandez, T.V. et al. Leveraging aggression risk gene expression in the developing and adult human brain to guide future precision interventions. Mol Psychiatry 26, 2680–2682 (2021). https://doi.org/10.1038/s41380-020-00903-3

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