Research Article: Genomic Architecture of Aggression: Rare Copy Number Variants in Intermittent Explosive Disorder

Date Published: December 02, 2011

Publisher: Wiley Subscription Services, Inc., A Wiley Company

Author(s): Tiffany H Vu, Emil F Coccaro, Evan E Eichler, Santhosh Girirajan.


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.

Partial Text

Recent analyses of copy number variants (CNVs) have revealed associations of genomic changes with a variety of human diseases and disorders. A majority of rare (frequency of <1%) CNVs arise within genomic “hotspots” due to unequal crossover between segmental duplications of high sequence identity [Lupski, 1998; Bailey et al., 2002]. Genome-wide surveys of these hotspots initially detected an enrichment of rare CNVs among individuals with intellectual disability [Sharp et al., 2006; Stankiewicz and Lupski, 2010] and were subsequently identified in individuals with schizophrenia [Walsh et al., 2008], autism [Sebat et al., 2007], obesity [Bochukova et al., 2010; Walters et al., 2010], and epilepsy [Helbig et al., 2009; Mefford and Mulley, 2010]. A total of 350 CNVs greater than 50 kbp were detected using array CGH among the 113 samples that passed DNA quality control measures (Supplementary Table I). At a similar rate of detection, 1,074 CNVs greater than 50 kbp were seen in our 306 NIMH controls (Supplementary Table II). Overall, there was no difference in the frequency of large CNVs (>500 kbp) between individuals with IED and controls (6/113 vs. 6/306, respectively; Fisher’s exact test, P = 0.072) assayed on the same microarray platform. After filtering for known copy number polymorphisms, we identified three large rare CNVs: a recurrent 1q21.1 deletion containing GJA8 [Brunetti-Pierri et al., 2008; Consortium, 2008; Mefford et al., 2008; Stefansson et al., 2008], a novel 16q22.3q23.1 deletion in individuals with IED, and an approximately 430-kbp 15q13.3 duplication containing CHRNA7 in an individual with PD (Table II). None of these events were observed in our 306 NIMH controls.

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]. We were particularly interested to see if 15q13.3 (BP4–BP5) deletions would be enriched in our subjects. Previous reports have emphasized the presence of neuropsychiatric disorders and neurobehavioral problems in patients with this particular alteration on chromosome 15q13.3 (Table II). We did not find any 15q13.3 (BP4–BP5) deletions in our cohort of 113 individuals; however, we recognize that the small sample size of our study cohort limits the power to detect this rare rearrangement. In a study of patients with schizophrenia, this deletion was found in 9/3,391 patients as opposed to 0/3,181 controls [Consortium, 2008]. Our results, therefore, do not completely rule out the possible association of this deletion with aggressive and impulsive behavior.




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