Abstract
Copy number variants (CNVs) are known to be associated with complex neuropsychiatric disorders (e.g., schizophrenia and autism) but have not been explored in the isolated features of aggressive behaviors such as intermittent explosive disorder (IED). IED is characterized by recurrent episodes of aggression in which individuals act impulsively and grossly out of proportion from the involved stressors. Previous studies have identified genetic variants in the serotonergic pathway that play a role in susceptibility to this behavior, but additional contributors have not been identified. Therefore, to further delineate possible genetic influences, we investigated CNVs in individuals diagnosed with IED and/or personality disorder (PD). We carried out array comparative genomic hybridization on 113 samples of individuals with isolated features of IED (n = 90) or PD (n = 23). We detected a recurrent 1.35-Mbp deletion on chromosome 1q21.1 in one IED subject and a novel ∼350-kbp deletion on chromosome 16q22.3q23.1 in another IED subject. While five recent reports have suggested the involvement of an ∼1.6-Mbp 15q13.3 deletion in individuals with behavioral problems, particularly aggression, we report an absence of such events in our study of individuals specifically selected for aggression. We did, however, detect a smaller ∼430-kbp 15q13.3 duplication containing CHRNA7 in one individual with PD. While these results suggest a possible role for rare CNVs in identifying genes underlying IED or PD, further studies on a large number of well-characterized individuals are necessary. © 2011 Wiley-Liss, Inc.
Highlights
We performed comparative genomic hybridization (CGH), using a custom whole-genome microarray targeted to genomic hotspots, to identify rare, potentially pathogenic copy number variants (CNVs) contributing to intermittent explosive disorder (IED) not present in 306 control individuals
At a similar rate of detection, 1,074 CNVs greater than 50 kbp were seen in our 306 National Institute of Mental Health (NIMH) controls (Supplementary Table II)
In this study we aimed to determine whether rare pathogenic CNVs are a predisposing factor for impulsive aggressive behavior, due to growing evidence that genomic architecture is highly significant to human biology and disease [Marques-Bonet et al, 2009; Mefford and Eichler, 2009]
Summary
Aggression is a complex behavior regulated and influenced by an individual’s environment, neural brain circuitry, and genetic makeup [Brunner et al, 1993; Manuck et al, 1999; Seroczynski et al, 1999; Volavka, 1999; Davidson et al, 2000; Bevilacqua et al, 2010]. Behavioral disorders have been reported in other patients with large CNVs including 1q21.1 cases with intellectual disability [Brunetti-Pierri et al, 2008] and 16p13.11 cases with autism [Ullmann et al, 2007], intellectual disability [Hannes et al, 2009], or schizophrenia [Ingason et al, 2009]. These findings suggest that haploinsufficiency of certain genomic regions affects specific neurobiological pathways predisposing individuals to aggressive and impulsive behavior. We assessed CNV data from a large set of 5,570 normal adult individuals matched for ethnicity [Consortium, 2008; Itsara et al, 2009]
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