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Cited by 98Neurotransmitter Receptor Influence on BehaviorGenetic Associations and EpidemiologyBullying, Victimization, and Aggression

An integrated analysis of genes and functional pathways for aggression in human and rodent models

Open access
Zhang-James, Yanli, Fernàndez-Castillo, Noèlia, Hess, Jonathan L, Malki, Karim, Glatt, Stephen J, Cormand, Bru, Faraone, Stephen V·2019·Molecular Psychiatry
DOI 10.1038/s41380-018-0068-7PMC PMC6274606
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Abstract

Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models, and two sets of genes with causal evidence from online Mendelian inheritance in man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons, and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression.

AI snapshot

Written from the paper’s full text.

TL;DR

This cross-species integrated analysis combined eight human and rodent aggression gene lists and found shared biological pathways plus a weighted top-40 gene set, while human GWAS and rodent transcriptome genes did not overlap significantly. ERBB4 was the only gene supported by all three evidence categories.

Key findings

  • The eight gene lists comprised 175 adult GWAS genes, 281 child GWAS genes, 89 KO-mouse genes, 381 Finland-mouse genes, 271 Holland-mouse genes, 397 USA-mouse genes, 85 OMIM genes, and 211 rat genes. Significant overlaps included adult/child GWAS sharing 6 genes (p = 0.038), KO mice sharing 4 genes with child GWAS (p = 0.037), 4 with OMIM (p = 0.001), 6 with Finland mice (p = 0.007), and 6 with rat (p < 0.0001); no aggression gene list overlapped significantly with the GWAS control set.
  • Seven canonical pathways were shared by all three main evidence categories: signaling by Rho family GTPases, ERK/MAPK signaling, G-protein-coupled receptor signaling, axonal guidance signaling, reelin signaling in neurons, molecular mechanisms of cancer, and Gαs signaling; GPCR signaling was also significantly enriched with the top-ranked genes (p = 0.002).
  • The weighted ranking produced 40 top-ranked genes, with MAOA ranked highest (weighted score 4), followed by ERBB4, GRIA3, MECP2, and PRNP (score 3); 23 of the top genes had KO-mouse reports, and RBFOX1 regulated 15 of the top 40 genes (p = 3.4e−05).
  • LDSC regression found significant positive genetic correlations between the EAGLE child aggression GWAS and ADHD (p = 9.75e−05), and between the antisocial behavior GWAS and ADHD (p = 4.4e−03) and MDD (p = 3.53e−03); no significant correlations were found with SCZ, ASD, BIP, or PTSD, or between the aggression GWAS meta-analyses.

Methods

  • Cross-species integration of eight gene lists: updated human GWAS genes from four adult and five child studies, reanalyzed rodent transcriptome data from four selectively bred models (Finland, Holland, and USA mice; rat) using weighted gene co-expression network analysis, and previously published OMIM (N = 85) and KO-mouse (N = 89) gene sets.
  • Gene overlap was tested with one-tailed Fisher’s exact tests; genes were ranked by a weighted sum: 1 × human GWAS occurrence + 0.5 × rodent transcriptome occurrence + 1.5 × OMIM/KO occurrence.
  • Pathway enrichment used Ingenuity Pathway Analysis, with multidimensional scaling of binary pathway enrichment, network analysis of the top 40 genes, and LD score regression for genetic correlations with six psychiatric disorders.

Limitations

  • The paper states that the approach inherits limitations of the original studies: GWAS were underpowered and may include false positives; KO-mouse studies are biased by authors’ choices; rodent models were defined by simple behavioral criteria that may not generalize; and OMIM genes may be more likely selected for KO, limiting assessment of true overlap.
  • The paper also states that non-genetic models and other organisms were not included, and that gene orthology and behavioral generalization across distant species remain difficult.
  • Evident from the text: many gene-overlap tests are reported as uncorrected p-values, and the adult aggression GWAS samples lacked sufficient sample sizes or summary statistics for LDSC analysis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41380-018-0068-7

Cites

Statistics

Claims the paper makes

0 of 70 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A total of 281 genes were selected from five children GWAS gene sets.

    “A total of 175 and 281 genes were selected from four adult and five children GWAS gene sets, respectively (Supplementary Figure 1 and Supplementary Table 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Six genes were present in both the adult and child GWAS gene sets: ALK, LAMA2, NFKB1, OSMR, RBFOX1, and WDR62 (significant overlap by Fisher's exact test, p = 0.038).

    “Six genes were present in both sets: ALK, LAMA2, NFKB1, OSMR, RBFOX1, and WDR62 (significant overlap by Fisher’s exact test, p = 0.038, Table 1).”
    Quote in the paperNot a substantial claim
  • Findingown data

    A total of 175 genes were selected from four adult GWAS gene sets.

    “A total of 175 and 281 genes were selected from four adult and five children GWAS gene sets, respectively (Supplementary Figure 1 and Supplementary Table 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    The 40 top-ranked genes are enriched for synapse (n = 11, GO: 0045202, p = 1e−08).

    “Forty of them have a weighted ranking score ≥2 (Table 2) and almost all are involved in neuronal functions: synaptic transmission (n = 13, GO: 0007268, p = 5e−09), nervous system development (n = 18, GO: 0007399, p = 7e−08), synapse (n = 11, GO: 0045202, p = 1e−08), neuron projection (n = 9, GO: 0043005, p = 2e−05), and neuroactive ligand–receptor interaction (n = 5, KEGG: 04080, p = 2e−04).”
    Quote in the paperSubstantial claim
  • Findingown data

    None of the eight aggression gene lists showed any significant overlap with the GWAS control gene set.

    “None of the eight aggression gene lists showed any significant overlap with the GWAS control gene set.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 13
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Only one gene was shared between the control GWAS gene list and either the adult (ARHGEF3) or child (LY86) aggression GWAS datasets, and this overlap was non-significant.

    “The control GWAS gene list comprises 172 genes (Supplementary Table 2); only one gene was shared with either the adult (ARHGEF3) or the child (LY86) datasets (non-significant).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For the mouse models, one module for each line was significantly downregulated in high-aggression versus low-aggression lines (Finland: ME12, uncorrected p-value <0.005, BH p-value <0.2; Holland: ME29, BH p < 0.05; USA: ME11, BH p < 0.05).

    “For the mouse models, one module for each line was significantly downregulated in high-aggression versus low-aggression lines (Finland: ME12, uncorrected p-value <0.005, BH p-value <0.2; Holland: ME29, BH p < 0.05; USA: ME11, BH p < 0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The Holland mice shared 12 genes with the USA lines (p = 0.013) and 13 with the Finland lines (p = 0.002).

    “The Holland mice shared 12 genes with the USA lines (p = 0.013) and 13 with the Finland lines (p = 0.002) (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No significant genetic correlations were found between the aggression GWAS meta-analyses and SCZ, ASD, BIP, or PTSD, or between the aggression GWAS meta-analyses.

    “No significant genetic correlations were found with any other disorders examined (SCZ, ASD, BIP, and PTSD), or between the aggression GWAS meta-analyses (Supplementary Figure 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The control GWAS gene list comprises 172 genes.

    “The control GWAS gene list comprises 172 genes (Supplementary Table 2); only one gene was shared with either the adult (ARHGEF3) or the child (LY86) datasets (non-significant).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The rat model shared five genes with the Finland and Holland lines (non-significant) and 10 with the USA lines (p = 0.01).

    “The rat model shared five genes with the Finland and Holland lines (non-significant) and 10 with the USA lines (p = 0.01).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The adult GWAS shared four pathways with the USA mouse and one with the rat model, and five pathways with the OMIM list.

    “The adult GWAS only shared four pathways with the USA mouse and one with the rat model, although it did share five pathways with the OMIM list.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The IPA activation Z-score analysis predicted mostly opposite activities between the USA mice and rat gene sets for shared canonical pathways, except for dopamine DARPP32 feedback in cAMP signaling, which was inhibited in both models.

    “The IPA activation Z-score analysis performed on the shared canonical pathways between the USA mice and rat gene sets predicted mostly opposite activities except for one: dopamine DARPP32 feedback in cAMP signaling. This pathway was inhibited in both models (Supplementary Figure 5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The percentage of enriched pathways shared with any other gene list out of total enriched canonical pathways were: OMIM 59%, USA mouse 53%, KO mice 48%, Child GWAS and Rat both 44%, adult GWAS 43%, Finland mouse 20% and Holland 11%.

    “The percentage of enriched pathways shared with any other gene list out of the total enriched canonical pathways for each list were ranked as follows: OMIM 59%, USA mouse 53%, KO mice 48%, Child GWAS and Rat both 44%, adult GWAS 43%, Finland mouse 20% and Holland 11%.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The USA mouse model mainly loaded in the fifth dimension, which accounted for an additional 8.6% of the variance.

    “The USA mouse model mainly loaded in the fifth dimension, which accounted for an additional 8.6% of the variance (not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These networks were related to nervous system development and function, neurological disease and psychological disorders, and cellular function and maintenance.

    “These networks were related to nervous system development and function, neurological disease and psychological disorders, and cellular function and maintenance (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither the EAGLE child sample nor Tielbeek's sample showed genetic correlations with SCZ, BIP, autism, or PTSD.

    “The lack of genetic correlations of either dataset with SCZ, BIP, autism, or PTSD”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The Finland and Holland lines had the lowest numbers of enriched pathways and overlap with other lists.

    “it is not surprising to see that they had the lowest numbers of enriched pathways and overlap with other lists.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The USA mice and rat lines shared <5% of genes, although the overlap was statistically significant.

    “However, their shared biological pathways often showed opposite inhibition/activation activities and, although statistically significant, the two lines shared <5% of genes (Table 1).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Twenty-three of the top 40 genes had reports of KO mice studies.

    “Twenty-three of the top genes had reports of KO mice studies, strongly supporting their role in aggression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Our top-ranked genes showed both high connectivity and enrichment with functional pathways relevant to brain functions.

    “We observed both characteristics for our top-ranked genes”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The heritability of human aggression has been estimated around 50%.

    “The heritability of human aggression has been estimated around 50% [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Tuvblad C, Baker LA. Human aggression across the lifespan: genetic propensities and environmental moderators. Adv Genet. 2011;75:171–214. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human aggression has a complex genetic architecture that interacts with environmental factors.

    “Its complex genetic architecture interacts with environmental factors [7–9].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Chen C, Liu C, Chen C, Moyzis R, Chen W, Dong Q. Genetic variations in the serotoninergic system and environmental factors contribute to aggressive behavior in Chinese adolescents. Physiol Behav. 2015;138:62–8. source

      Not checked in the free run.

    • cites [8] Kendler KS, Ohlsson H, Morris NA, Sundquist J, Sundquist K. A Swedish population-based study of the mechanisms of parent-offspring transmission of criminal behavior. Psychol Med. 2015;45:1093–102. source

      Not checked in the free run.

    • cites [9] Laucht M, Brandeis D, Zohsel K. Gene-environment interactions in the etiology of human violence. Curr Top Behav Neurosci. 2014;17:267–95. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study used a negative control gene list from 14 phenotypes not related to the nervous system, with sample sizes similar to the nine aggression GWAS, to retrieve associated signals and nearby genes.

    “As a negative control, we generated a gene list from the GWAS catalog (https://www.ebi.ac.uk/gwas/) by combining signals from 14 phenotypes not related to the nervous system in samples of individuals with European ancestry and sample sizes that are similar to those of the nine GWAS of aggressive behaviors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LRRC7 interacts with cytoskeleton molecules and is involved in synaptic spine structure and patterning.

    “LRRC7 interacts with cytoskeleton molecules and is involved in synaptic spine structure and patterning [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Vessey JP, Karra D. More than just synaptic building blocks: scaffolding proteins of the post-synaptic density regulate dendritic patterning. J Neurochem. 2007;102:324–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rare mutations in the gene encoding MeCP2 cause Rett syndrome, mental retardation, and increased aggression.

    “For example, rare mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), a chromatin-associated protein involved in transcription regulation, cause Rett syndrome, mental retardation, and increased aggression [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Gomot M, Gendrot C, Verloes A, Raynaud M, David A, Yntema HG, et al. MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation. Am J Med Genet A. 2003;123A:129–39. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutation of the prion protein gene causes inherited prion diseases and aggressive behavior in humans.

    “Another example is the gene for prion protein, the mutation of which causes inherited prion diseases and aggressive behavior in humans [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Nitrini R, Rosemberg S, Passos-Bueno MR, da Silva LS, Iughetti P, Papadopoulos M, et al. Familial spongiform encephalopathy associated with a novel prion protein gene mutation. Ann Neurol. 1997;42:138–46. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The sample size of children in Tielbeek's GWAS was likely too small for LDSC regression, explaining the lack of genetic correlation despite the presence of children samples in both datasets.

    “likely too small for LDSC regression and explaining their lack of correlation despite the presence of children samples in both datasets.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The two main categories, human GWAS genes and rodent transcriptome genes, did not overlap significantly, although they both shared significant overlap with distinct subsets of high-risk genes.

    “The two main categories, human GWAS genes and rodent transcriptome genes, however, did not overlap significantly, although they both shared significant overlap with distinct subsets of the high-risk genes (those obtained from human OMIM phenotypes and KO mice).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: A cross-species and integrated approach combining different modalities of genetic data yields a clearer understanding of the genetics of aggression.
    • The authors state this as an assumption: The convergence of evidence by cross-referencing and integrating available data leads to a more comprehensive and confident understanding of the genetic basis of aggression in humans and mammals.

  • May combine two claims.

    Interpretationreasoning

    The results highlight possible genetic differences between the adult and child GWAS sets, although this may be due to phenotype differences between the two samples.

    “More importantly, the results highlight the possible genetic differences, although it may be due to phenotype differences between the two samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The pattern suggests differences in the genetic etiology of human and rodent aggression or the possibility that human GWAS and transcriptomic studies of rodent brains capture different sets of genes involved in the etiology of aggression.

    “This suggests differences in the genetic etiology of human and rodent aggression or the possibility that human GWAS and transcriptomic studies of rodent brains capture different sets of genes involved in the etiology of aggression.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: A cross-species and integrated approach combining different modalities of genetic data yields a clearer understanding of the genetics of aggression.
    • The authors state this as an assumption: The convergence of evidence by cross-referencing and integrating available data leads to a more comprehensive and confident understanding of the genetic basis of aggression in humans and mammals.
    • Rests on an assumption: Rodent models of aggression and their transcriptome changes are relevant to human aggression genetics.

  • May combine two claims.

    Premisecitation

    The Finland and Holland lines were selectively bred based on a single behavioral criterion, either increased aggression toward non-aggressive mice or decreased attack latency toward intruder mice.

    “Considering that the Finland and Holland lines were selectively bred based on a single behavioral criterion, either increased aggression toward non-aggressive mice [40] or decreased attack latency toward intruder mice [41]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Lagerspetz K. Genetic and social causes of aggressive behaviour in mice. Scand J Psychol. 1961;2:167–73. source

      Not checked in the free run.

    • cites [41] van Oortmerssen GA, Bakker TC. Artificial selection for short and long attack latencies in wild Mus musculus domesticus. Behav Genet. 1981;11:115–26. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The results support pleiotropic effects of shared common DNA variants on the comorbidity of aggression with ADHD in children, or with MDD in adults.

    “The results support pleiotropic effects of shared common DNA variants on the comorbidity of aggression with ADHD in children, or with MDD in adults.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aggressive behaviors often manifest in different forms and are triggered by different risk factors across the lifespan.

    “Indeed, aggressive behaviors often manifest in different forms and are triggered by different risk factors across the lifespan [60].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Liu J, Lewis G, Evans L. Understanding aggressive behaviour across the lifespan. J Psychiatr Ment Health Nurs. 2013;20:156–68. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adult onset aggression is often linked to physical or emotional trauma, substance use, medical illnesses, or brain injuries.

    “Adult onset aggression is often linked to physical or emotional trauma, substance use, medical illnesses, or brain injuries [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Liu J, Lewis G, Evans L. Understanding aggressive behaviour across the lifespan. J Psychiatr Ment Health Nurs. 2013;20:156–68. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Axonal guidance and reelin signaling are important pathways for nervous system development and have been implicated in neuropsychiatric disorders such as bipolar, SCZ, and ADHD.

    “Axonal guidance and reelin signaling are important pathways for nervous system development and have been implicated in neuropsychiatric disorders such as bipolar, SCZ, and ADHD [64–68]”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [64] Mooney MA, McWeeney SK, Faraone SV, Hinney A, Hebebrand J, Consortium I, et al. Pathway analysis in attention deficit hyperactivity disorder: an ensemble approach. Am J Med Genet B Neuropsychiatr Genet. 2016;171:815–26. source

      Not checked in the free run.

    • cites [65] Chen N, Bao Y, Xue Y, Sun Y, Hu D, Meng S, et al. Meta-analyses of RELN variants in neuropsychiatric disorders. Behav Brain Res. 2017;332:110–9. source

      Not checked in the free run.

    • cites [66] Li W, Guo X, Xiao S. Evaluating the relationship between reelin gene variants (rs7341475 and rs262355) and schizophrenia: a meta-analysis. Neurosci Lett. 2015;609:42–7. source

      Not checked in the free run.

    • cites [67] Chen SY, Huang PH, Cheng HJ. Disrupted-in-schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling. Proc Natl Acad Sci USA. 2011;108:5861–6. source

      Not checked in the free run.

    • cites [68] Goes FS, Willour VL, Zandi PP, Belmonte PL, MacKinnon DF, Mondimore FM, et al. Sex-specific association of the reelin gene with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:549–53. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Human disease genes tend to interact with each other with higher network connectivity than non-disease genes.

    “Human disease genes tend to interact with each other with higher network connectivity than non-disease genes [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Ideker T, Sharan R. Protein networks in disease. Genome Res. 2008;18:644–52. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It is not uncommon for cancer patients to display changed personalities and even violent behaviors.

    “it is not uncommon for cancer patients to display changed personalities and even violent behaviors [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Grube M. Violent behavior in cancer patients--a rarely addressed phenomenon in oncological treatment. J Interpers Violence. 2012;27:2163–82. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The close relationship of cancer signaling with the immune system offers a plausible mechanism linking cancer with many neuropsychiatric conditions including aggression.

    “The close relationship of cancer signaling with immune system offers a plausible mechanism linking cancer with many neuropsychiatric conditions including aggression.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Cancer signaling has never been implicated in aggression.
    • Rests on an assumption: Cancer signaling has a close relationship with the immune system.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Many studies of complex neuropsychiatric disorders have concluded that disease-causing variants are often clustered in protein-interaction networks with a high degree of connectivity among themselves and that these clustered networks are often enriched with functional pathways relevant to brain functions.

    “Many studies of complex neuropsychiatric disorders have also concluded that disease-causing variants are often clustered in protein-interaction networks with a high degree of connectivity among themselves and that these clustered networks are often enriched with functional pathways relevant to brain functions [72–80].”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [72] Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–5. source

      Not checked in the free run.

    • cites [73] Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–41. source

      Not checked in the free run.

    • cites [74] O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43:585–9. source

      Not checked in the free run.

    • cites [75] O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science. 2012;338:1619–22. source

      Not checked in the free run.

    • cites [76] Ben-David E, Shifman S. Networks of neuronal genes affected by common and rare variants in autism spectrum disorders. PLoS Genet. 2012;8:e1002556. source

      Not checked in the free run.

    • cites [77] Sakai Y, Shaw CA, Dawson BC, Dugas DV, Al-Mohtaseb Z, Hill DE, et al. Protein interactome reveals converging molecular pathways among autism disorders. Sci Transl Med. 2011;3:86ra49. source

      Not checked in the free run.

    • cites [78] Lanz TA, Guilmette E, Gosink MM, Fischer JE, Fitzgerald LW, Stephenson DT, et al. Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action. Mol Autism. 2013;4:45. source

      Not checked in the free run.

    • cites [79] Poelmans G, Pauls DL, Buitelaar JK, Franke B. Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. Am J Psychiatry. 2011;168:365–77. source

      Not checked in the free run.

    • cites [80] Yang L, Neale BM, Liu L, Lee SH, Wray NR, Ji N, et al. Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. Am J Med Genet B Neuropsychiatr Genet. 2013;162:419–30. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Genes reported to cause aggression in OMIM disorders may be more likely selected for gene KO in animal models.

    “genes reported to cause aggression in OMIM disorders may be more likely selected for gene KO in animal models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The observation of both characteristics for our top-ranked genes strongly supports a multifactorial genetic landscape for aggression and the roles of these top genes in aggression.

    “We observed both characteristics for our top-ranked genes, which strongly supports a multifactorial genetic landscape for aggression and the roles of these top genes in aggression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    GWAS were underpowered and the resulting gene sets may include many false positives.

    “GWAS were underpowered and the resulting gene sets may include many false positives.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Although KO models validate the role of these genes in aggression, they limit our ability to understand the true degree of overlap.

    “Although these KO models validate the role of these genes in aggression, it limits our ability to understand the true degree of overlap.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Non-genetic models, such as stress-induced aggression and other organisms, were not included in this study.

    “We noted that non-genetic models, such as stress-induced aggression [27, 81] and other organisms [30, 31, 82], were not included in this study.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [27] Malki K, Tosto MG, Pain O, Sluyter F, Mineur YS, Crusio WE, et al. Comparative mRNA analysis of behavioral and genetic mouse models of aggression. Am J Med Genet B Neuropsychiatr Genet. 2016;171B:427–36. source

      Not checked in the free run.

    • cites [81] Muhie S, Gautam A, Meyerhoff J, Chakraborty N, Hammamieh R, Jett M. Brain transcriptome profiles in mouse model simulating features of post-traumatic stress disorder. Mol Brain. 2015;8:14. source

      Not checked in the free run.

    • cites [30] Malki K, Du Rietz E, Crusio WE, Pain O, Paya-Cano J, Karadaghi RL, et al. Transcriptome analysis of genes and gene networks involved in aggressive behavior in mouse and zebrafish. Am J Med Genet B Neuropsychiatr Genet. 2016;171:827–38. source

      Not checked in the free run.

    • cites [31] Kudo A, Shigenobu S, Kadota K, Nozawa M, Shibata TF, Ishikawa Y, et al. Comparative analysis of the brain transcriptome in a hyper-aggressive fruit fly, Drosophila prolongata. Insect Biochem Mol Biol. 2017;82:11–20. source

      Not checked in the free run.

    • cites [82] Zapata I, Serpell JA, Alvarez CE. Genetic mapping of canine fear and aggression. BMC Genomics. 2016;17:572. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The rodent genetic models had been defined by simple behavioral criteria, which may not be generalizable to other species.

    “The rodent genetic models had been defined by simple behavioral criteria, which may not be generalizable to other species.”
    Quote in the paperNot a substantial claim
41 of 41

  • The authors state this as an assumption.

    A cross-species and integrated approach combining different modalities of genetic data yields a clearer understanding of the genetics of aggression.

    “Meanwhile, we postulate that a cross-species and integrated approach combining different modalities of genetic data can yield a clearer understanding of the genetics of aggression.”

  • The authors state this as an assumption.

    The convergence of evidence by cross-referencing and integrating available data leads to a more comprehensive and confident understanding of the genetic basis of aggression in humans and mammals.

    “Although each of these studies have intrinsic limitations, the convergence of evidence by cross-referencing and integrating the available data may lead to a more comprehensive and confident understanding of the genetic basis of aggression in humans and mammals.”

  • The paper relies on this without support.

    Rodent models of aggression and their transcriptome changes are relevant to human aggression genetics.

    “Genome-wide transcriptome data were available for four genetic rodent models of aggression: three inbred mouse strains [28] and one rat strain [29] along with their comparable low-aggression strains.”

  • The paper relies on this without support.

    Human aggression is often accompanied by traits such as increased reactivity, novelty exploration, impulsivity, and vulnerability to psychostimulant abuse.

    “Considering that human aggression is often accompanied by these traits”

  • The paper relies on this without support.

    OMIM phenotypes are typically multidimensional, including medical, psychiatric, and aggressive features, and it was previously unclear whether aggression in affected individuals was a direct genetic effect or mediated via another phenotype.

    “Because the OMIM phenotypes are typically multidimensional phenotypes including medical, psychiatric, and aggressive features, it has not heretofore been clear whether the aggression observed in affected individuals was a direct genetic effect or if it was mediated via another phenotype.”

  • The paper relies on this without support.

    GPCR signaling mediates receptor signaling including serotonin, dopamine, metabotropic glutamate, oxytocin, and vasopressin receptors.

    “the GPCR signaling pathway, which was significantly enriched in our data (Table 3), mediates much receptor signaling including serotonin, dopamine, metabolic glutamate receptors, oxytocin and vasopressin receptors.”

  • The paper relies on this without support.

    ERK/MAPK and Rho-GTPase signaling form intracellular signaling cascades that orchestrate cellular responses of GPCR signaling.

    “ERK/MAPK and Rho-GTPase signaling form intracellular signaling cascades that orchestrate cellular responses of GPCR signaling.”

  • The paper relies on this without support.

    Bipolar, SCZ, and ADHD are often associated with aggression.

    “which are often associated with aggression.”

  • The paper relies on this without support.

    Cancer signaling has never been implicated in aggression.

    “Although it has never been implicated in aggression”

  • The paper relies on this without support.

    Cancer signaling has a close relationship with the immune system.

    “The close relationship of cancer signaling with immune system”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Zhang-James et al. [36] reported a modest gene overlap between different categories of genetic evidence (human GWAS, genes with known causal evidence and rodent transcriptome genes).

    “Similarly, Zhang-James et al. [36] reported a modest gene overlap between different categories of genetic evidence (human GWAS, genes with known causal evidence and rodent transcriptome genes).”

    From Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle (2021) · cites this paper as [36]

  • Zhang-James et al. [36] identified ERK/MAPK signaling as mechanisms underlying aggression.

    “Similar results were obtained by Zhang-James et al. [36], who also identified ERK/MAPK signaling as mechanisms underlying aggression.”

    From Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle (2021) · cites this paper as [36]

  • Malki et al. [36] observed that the MAPK signaling pathway was differentially expressed between aggressive and non-aggressive lines in mouse models.

    “Malki et al. [36] performed a genome-wide transcriptome analysis of mouse models of aggression and also observed that the MAPK signaling pathway was differentially expressed between the aggressive and non-aggressive lines.”

    From Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle (2021) · cites this paper as [36]

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(1, 22) = 10.59reported p = .004 · recomputed p = .004

    “F(1, 22) = 10.59, p = .004”

  • ConsistentF(1, 28) = 4.97reported p = .034 · recomputed p = .034

    “F(1, 28) = 4.97, p = .034”

2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

The citation lists haven’t been fetched yet

References 80 · Cited by 98

Research works printed but not linked: 2

  1. Zhang B, Srihari SN. Properties of binary vector dissimilarity measures. InProc. JCIS Int’l Conf. computer vision, pattern recognition, and image processing 2003; Vol. 1.
  2. Zhang-James Y, Faraone SV. Genetic architecture for human aggression - a study of gene-phenotype relationship in OMIM. World Congress of Psychiatric Genetics - WCPG 2015: Toronto; 2015. · DOI · Paper page

Authors
Zhang-James, Y., Fernàndez-Castillo, N., Hess, J. L., Malki, K., Glatt, S. J., Cormand, B., & Faraone, S. V.
Affiliations
  • SUNY Upstate Medical University (US)
  • King's College London (GB)
  • Centre for Biomedical Network Research on Rare Diseases (ES)
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-06-01
Volume
24
Issue
11
Pages
1655-1667
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-018-0068-7
PMC
PMC6274606
OpenAlex
W2807374598
Semantic Scholar
f1141bd438bdac7f5805efe0fa99ce2bbf604a0c
Cited by
98
References
80
Citations by year
2026: 4 · 2025: 8 · 2024: 16 · 2023: 7 · 2022: 21 · 2021: 17 · 2020: 12 · 2019: 11 · 2018: 2
FWCI
4.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
Funders
  • European Commission (2014‐2020, 2007–2013, FP7 2007-2013, HORIZON2020, H2020, FP7/2007, H2020/2014-2020, 667302, 602805)
  • Generalitat de Catalunya (2017-SGR, 2017/SGR738)
  • Ministerio de Economía y Competitividad (SAF2015-68341-R)
  • Universitetet i Bergen
  • European College of Neuropsychopharmacology
  • Horizon 2020 Framework Programme (H2020/2014–2020, FP7/2007-2013, 667302)
  • Agència de Gestió d'Ajuts Universitaris i de Recerca (2014-2020, 2017-SGR-738)
  • National Institute of Mental Health (U01MH109536, R01MH101519)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Social Sciences › Psychology › Social Psychology › Bullying, Victimization, and Aggression
Keywords
aggression, genetic architecture, gene list, pathway enrichment, G protein-coupled receptor signaling, axon guidance, Reelin signaling, ERK signaling, knockout mice, OMIM, cross-species comparison, risk genes
MeSH terms
Reelin Protein, Aggression, Animals, Emotions, Humans, Risk Factors, Stress, Physiological, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Expression Profiling, Databases, Genetic, Mice, Rats, Gene Regulatory Networks, Genome-Wide Association Study, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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