RBFOX1, encoding a splicing regulator, is a candidate gene for aggressive behavior

Abstract

The RBFOX1 gene (or A2BP1) encodes a splicing factor important for neuronal development that has been related to autism spectrum disorder and other neurodevelopmental phenotypes. Evidence from complementary sources suggests that this gene contributes to aggressive behavior. Suggestive associations with RBFOX1 have been identified in genome-wide association studies (GWAS) of anger, conduct disorder, and aggressive behavior. Nominal association signals in RBFOX1 were also found in an epigenome-wide association study (EWAS) of aggressive behavior. Also, variants in this gene affect temporal lobe volume, a brain area that is altered in several aggression-related phenotypes. In animals, this gene has been shown to modulate aggressive behavior in Drosophila. RBFOX1 has also been associated with canine aggression and is upregulated in mice that show increased aggression after frustration of an expected reward. Associated common genetic variants as well as rare duplications and deletions affecting RBFOX1 have been identified in several psychiatric and neurodevelopmental disorders that are often comorbid with aggressive behaviors. In this paper, we comprehensively review the cumulative evidence linking RBFOX1 to aggression behavior and provide new results implicating RBFOX1 in this phenotype. Most of these studies (genetic and epigenetic analyses in humans, neuroimaging genetics, gene expression and animal models) are hypothesis-free, which strengthens the validity of the findings, although all the evidence is nominal and should therefore be taken with caution. Further studies are required to clarify in detail the role of this gene in this complex phenotype.

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

“…Interestingly, the protein encoded by RBFOX1 regulates the expression of 15 of the top 40 ranked genes (the probability of this event is p=3.4e-05) 70 . Convergent data from GWAS, neuroimaging genetics, epigenetics, gene expression and animal models supports RBFOX1 as a strong candidate for aggression 57 . Furthermore, all 40 genes are highly connected in three functional networks ( Figure 2 ).…”

“…NFKB1 is a transcription factor involved in regulating responses of neurons to activation of different signaling pathways in a variety of physiological and pathological conditions 55 . RBFOX1 is a splicing factor implicated in many neurodevelopmental and psychiatric disorders and several evidences have highlighted this gene as a candidate for aggression 56 , 57 . WDR62 is a centrosomal and nuclear protein linked to autosomal recessive microcephaly 58 , 59 .…”

Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

“…4b). Animal models and association studies have implicated RBFOX1 in aggressive behaviors, a trait observed in several of the disorders in our analysis (Fernandez-Castillo et al, 2017).…”

“…4b). Animal models and association studies have implicated RBFOX1 in aggressive behaviors, a trait observed in several of the disorders in our analysis (Fernandez-Castillo et al, 2017).Of the 109 pleiotropic loci, 76 were identified in the GWAS of individual disorders, while the remaining 33 are novel. The most pleiotropic among these novel loci was a region downstream of NOX4 (NADPH Oxidase 4) that was associated with SCZ, BIP, MD, ASD, and AN (rs117956829; Pmeta = 1.82 x 10 -9 ; Fig.…”

From rare Copy Number Variations to biological processes in ADHD

“…(62–65) Animal models have shown that RBFOX1 is involved in mouse corticogenesis and aggressive behaviours. (62,64,66,67) POLR3C is included in a well-known small CNV located at 1q21.1, which contributes to a broad spectrum of phenotypes in addition to ADHD, including morphological features and autism spectrum disorders (ASD). (68,69) Genes listed in Table 1 may be viewed as having, individually, the highest credibility as ADHD candidate genes.…”