REVIEW ARTICLE

Neuropsychiatric Genetics Aggressive Behavior in Humans: Genes and Pathways Identified Through Association Studies Noelia Fernandez-Castillo1,2,3* and Bru Cormand1,2,3* 1Departament de Genetica, Facultat de Biologia, Universitat de Barcelona, Catalonia, Spain 2Institut de Biomedicina de la Universitat de Barcelona (IBUB), Catalonia, Spain 3Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Spain

Manuscript Received: 26 June 2015; Manuscript Accepted: 4 January 2016

Aggressive behavior has both genetic and environmental com- ponents. Many association studies have been performed to How to Cite this Article: identify genetic factors underlying aggressive behaviors in Fernandez-Castillo N, Cormand B. 2016. humans. In this review we summarize the previous work per- Aggressive Behavior in Humans: Genes and formed in this field, considering both candidate gene (CGAS) Pathways Identified Through Association and genome-wide association studies (GWAS), excluding those Studies. performed in samples where the primary diagnosis is a psychi- atric or neurological disorder other than an aggression-related Am J Med Genet Part B 171B:676–696. phenotype. Subsequently, we have studied the enrichment of pathways and functions in GWAS data. The results of our searches show that most CGAS have identified associations and related to reduced emotional sensitivity, often without remorse with genes involved in dopaminergic and serotonergic neuro- or regret, whereas reactive aggression is related to excessive emo- transmission and in hormone regulation. On the other hand, tional sensitivity and an overreaction towards threat perception, GWAS have not yet identified genome-wide significant associ- triggered by negative emotions, anger, anxiety or bad experiences ations, but top nominal findings are related to several signaling [Robinson and Wilkowski, 2010]. pathways, such as axon guidance or estrogen receptor signaling, Aggressive behavior and the inability to control aggressive and also to neurodevelopmental processes and synaptic plastic- impulses seem to be influenced by both genetic and environmental ity. Future studies should use larger samples, homogeneous factors. A number of twin and adoption studies have investigated phenotypes and standardized measurements to identify genes the genetic and environmental architecture of aggressive behavior, that underlie aggressive behaviors in humans. including several meta-analyses. Taken together, they show that Ó 2016 Wiley Periodicals, Inc. about 50% of the variance in aggression is explained by genetic influences and the remaining 50% is explained by environmental Key words: aggression; genetics; association studies; GWAS; factors not shared by family members [Tuvblad and Baker, 2011]. candidate genes Age and form of aggression (reactive, proactive, direct/physical, indirect/relational) have an influence on these figures, whereas they seem to be sex-independent, although males are more likely than INTRODUCTION Conflicts of interest: The authors declare no conflicts of interest. Fromanevolutionarypointofview,aggressivebehavior inanimalsis Grant sponsor: Centro de Investigacion Biomedica en Red de related to individual fitness since it enables surviving and mating Enfermedades Raras (CIBERER); Grant sponsor: Spanish “Ministerio when competing for limited resources, defending from predators de Economı´a y Competitividad”; Grant number: SAF2012-33484; and establishing hierarchies. In social animals, both low and high Grant sponsor: AGAUR; Grant number: 2014SGR932; Grant sponsor: levels of aggression are detrimental for surviving, and aggressive European Community’s Seventh Framework Programme; Grant number: 602805. behavior may be under stabilizing selection [Anholt and Mackay, 2012]. Similarly, in humans, aggressive behavior has some advan- Correspondence to: Noelia Fernandez Castillo and Bru Cormand, Departament de Genetica, tages in competition, reproduction and dominance in hierarchy, but Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal 643, when expressed in the wrong context it may lead to injury or death edifici Prevosti, 3ª planta, 08028, Barcelona, Catalonia, Spain. and cause serious social problems, especially when this behavior is E-mail: [email protected] (N.F.-C.); [email protected] (B.C.) impulsive and uncontrolled or deliberate and premeditate. Article first published online in Wiley Online Library Human aggressive behavior has been usually classified in pro- (wileyonlinelibrary.com): 15 January 2016 active and reactive aggression. Proactive aggression is premeditated DOI 10.1002/ajmg.b.32419

Ó 2016 Wiley Periodicals, Inc. 676 FERNANDEZ-CASTILLO AND CORMAND 677 females to show aggressive behaviors. Regarding age, the genetic the six genome-wide association studies (GWAS) meeting the influences become increasingly more important at later stages in inclusion criteria described above. For that purpose we asked life (e.g., from 55% at 1–5 years to 63% at 11–18 years) (see a meta- the authors of these studies to provide us with the data on analysis by Burt [2009]). Adoption and twin studies also show that associated SNPs in their GWAS studies, considering a threshold the genetic effects on the aggressive phenotype depend upon set at P ¼ 5e-05. For the study performed in hostility by Merjonen environmental factors (GXE) such as family adversity and antiso- et al. [2011] we only included signals associated with anger, cial disadvantage, violent media exposure or alcohol use [Craig, considering mean values across the four measures, whereas signals 2007; Craig and Halton, 2009; Tuvblad and Baker, 2011; Pavlov associated with cynicism and paranoia were discarded. For the et al., 2012]. study performed by Anney et al. [2008] we considered associations Based on the substantial genetic component that underlies only under the additive model, and not under the other genetic aggressive behavior, several linkage and association studies have models tested. For the study of Mick et al. [2014] we included been performed to identify genes that participate in modulating associations with anger, considering both angry temperament and human aggressive behavior. In this review we have focused on genes angry reaction measures. Finally, for the study of Viding et al. involved in human aggressive behavior identified through associ- [2010] a complete list of p-values from the discovery sample was ation studies that assessed this phenotype as a dimensional trait not available. However, as the study included a replication sample, (externalizing behavior, anger, delinquency, criminality, violence) we considered the top 30 replicated signals reported in the paper. A or as a diagnostic category (conduct disorder, oppositional defiant total of 559 signals were selected across the six GWAS [Anney et al., disorder, callous unemotional, and antisocial personality), and 2008; Viding et al., 2010; Merjonen et al., 2011; Mick et al., 2011, aimed at identifying pathways that underlie this complex behavior. 2014; Tielbeek et al., 2012]. We used the PLINK software to retrieve information of the nearby genes for each of those SNPs, consider- ing a window of 100 Kb distal and proximal from each SNP. When Literature Searches and Bioinformatic Analyses more than one gene was present in the window, we chose only the In this review we have focused on aggressive behaviors including one closest to the SNP. A total of 156 genes were finally included, aggression traits (aggressiveness, impulsive aggression, anger, ex- two of them, A2BP1 and NFKB1, being identified in two different ternalizing behavior, violence, delinquency or criminality) or studies (see Fig. 1). To identify over-representation of pathways diagnostic categories (oppositional defiant disorder [ODD], con- and functions among the genes associated with aggressive behavior duct disorder [CD], antisocial behavior or antisocial personality we used WebGESTALT (http://bioinfo.vanderbilt.edu/webgestalt) disorder [ASPD], callous unemotional [CU], and psychopathy), and the Ingenuity Pathway Analysis (IPA) 8.8 software (Ingenuity and have discussed them separately. We have not considered Systems, Redwood city, CA, USA). Pathway enrichment was studies performed in samples with other psychiatric or neurologi- performed using KEGG pathways and Common pathways analyses cal disorders (e.g., drug use or dependence, bipolar disorder, of WebGESTALT. Function over-representation was performed schizophrenia, major depression). using the Gene Ontology (GO) analysis of WebGESTALT and Bibliography included in this review considered searches Diseases and Bio Functions analysis of IPA. Finally, gene network performed by Vassos et al. [2014] and Gunter et al. [2010]. analyses were performed with IPA. To update their searches from December 2009 until Febru- ary 2015 we searched in PubMed using the terms “(aggression Genetic Association Studies of Aggressive OR aggressivity OR aggressive OR anger OR hostility OR irrita- bility OR violence OR convict OR crimin OR offend OR Behavior externalizing OR conduct OR antisocial OR impulsive aggression Association studies performed to identify genetic variants involved OR psychopathy OR ODD OR oppositional defiant OR callous in the susceptibility to aggression have followed two different unemotional) AND (genetics OR gene OR polymorphism OR approaches: candidate gene association studies (CGAS) or genotype OR allele OR genome OR haplotype)”, with an output genome-wide association studies (GWAS). Most of the studies of 7,202 articles. We filtered articles written in English, per- examining aggressive behavior traits and phenotypes have focused formed in humans, including sample characteristics and per- on candidate genes, based on previous evidence or biological forming genetic association studies. We selected 268 potential plausibility. The majority of investigated genes encode proteins articles within those dates and added 263 articles from a previous involved in dopamine or serotonin neurotransmission as well as review [Gunter et al., 2010] and from a meta-analysis [Vassos hormone enzymes or receptors. In contrast, only a few GWAS scans et al., 2014]. From these 531 articles we selected those studies that have been performed so far, which assess different phenotypes included traits related to aggression or diagnostic categories related to aggressive behaviors. The genome-wide hypothesis-free specified above, excluding studies performed in samples of approach has allowed identification of several genes that had not individuals with other psychiatric disorders. A total of 277 been considered in CGAS and highlight novel pathways and articles were finally considered for this review. In order to functions potentially relevant to these behaviors. minimize possible sources of clinical and etiological heterogene- The most studied variants in CGAS have often shown conflicting ity, the results of reports that assess traits of aggression or specific association results in the different reports, so meta-analytical diagnostic categories are discussed separately. approaches have been used to try to clarify their contribution For bioinformatic analyses aimed at identifying functions and to aggression. The most comprehensive meta-analysis investigated pathways involved in aggressive behaviors we considered data of 31 genes from 185 studies and did not identify any significant 678 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

FIG. 1. Selection of variants and genes associated with aggressive behavior from GWAS studies. The criteria for the selection of association signals and the number of genes associated within a window of 100 kb from each SNP are indicated. A total of 156 genes showing a nominal association with aggressive behavior were selected, two of them in two independent studies.

association [Vassos et al., 2014]. However, there was a remarkable involved in the metabolism of these neurotransmitters (MAOA heterogeneity in the phenotypes assessed, as the study included and COMT), the serotonin transporter (5HTT) and a dopamine samples with psychiatric or neurological diseases (such as sub- receptor (DRD4), but other genes have also been investigated stance use disorders, schizophrenia, Alzheimer or intellectual (Tables I and II). We will first discuss studies performed on genes disability) that may drive the aggression behaviors, biasing the coding for enzymes involved in the metabolism of both dopamine results. In this review we have not considered studies performed in andserotonin,thenwewillfocusonserotonergicgenes,andfinally samples with other psychiatric or neurological disorders. on dopaminergic genes. The MAOA gene encodes monoamine oxidase A, an enzyme responsible for the catabolism of amines (dopamine, serotonin and Candidate Gene Association Studies (CGAS) noradrenalin). This gene is located on chromosome X and most of Since the identification in 1993 of a truncating mutation in the X- the published studies have been performed in male samples or have linked MAOA gene responsible for a severe aggressive and violent identified associations in males. Results obtained in females are behavior in the male individuals of a Dutch family [Brunner et al., difficult to interpret because of the lack of information on chro- 1993], and the confirmation that Maoa knock-out mice show mosome X inactivation. An upstream variable number of tandem aggressive behaviors [Cases et al., 1995], dopamine and serotonin repeats polymorphism (uVNTR) located in the promoter region neurotransmission have been the main focus of aggression studies. and with a repeat unit length of 30 bp, has been the most studied On the other hand, gender-specific genes and genes related to genetic variant in aggressive behaviors. Low activity alleles of this hormonal function (e.g., hormone metabolizers or receptors) have VNTR (2 and 3 repeats), which determine reduced transcriptional also received attention, since aggressive behavior is more frequent levels, have been associated with aggressive behavior, increased in males. Genetic factors involved in aggressive behavior are likely traits of aggression or high aggression scores, aggressiveness and to have a small effect size, and may contribute to the phenotype in impulsivity, reactive aggressiveness, violent behavior, delinquency, some cases in combination with specific environmental factors. For use of weapons, stabbing and shooting [Manuck et al., 2000, 2002; this reason, several association studies assess gene by environmen- Eisenberger et al., 2007; Reif et al., 2007; Guo et al., 2008; Beaver tal interactions (G E). et al., 2010a, 2014; Gallardo-Pujol et al., 2013; Kuepper et al., 2013; Dopamine and serotonin neurotransmission. The four most Tiihonen et al., 2015]. Also, studies considering GxE interactions studied genes related to dopamine and serotonin encode enzymes showed that the low activity variant in the VNTR interacts with FERNANDEZ-CASTILLO AND CORMAND 679

TABLE I. Candidate Genes Investigated in Aggressive Traits

References (positive and negative Gene symbol Gene name Associated phenotype associations) ABCG1 ATP-binding cassette, sub-family G Aggression and anger Gietl et al. [2007] (WHITE), member 1 AKAP5 A kinase (PRKA) anchor protein 5 Anger Richter et al. [2011] ANK3 ankyrin 3, node of Ranvier (ankyrin G) Externalizing behavior Logue et al. [2013] AP2B transcription factor AP-2 beta (activating Aggression Damberg et al. [2000] enhancer binding protein 2 beta) AR androgen receptor Violent criminal behavior, aggression Cheng et al. [2006]; Jonsson et al. [2001]; Rajender et al. [2008] AVP arginine vasopressin Aggression Malik et al. [2014] AVPR1A arginine vasopressin receptor 1A Aggression and anger Malik et al. [2014]; Moons et al. [2014] AVPR1B arginine vasopressin receptor 1B Aggression Luppino et al. [2014]; Zai et al. [2012b] BDNF brain-derived neurotrophic factor Aggressive behavior, aggression and Kretschmer et al. [2014]; Musci et al. impulsivity [2014]; Perroud et al. [2010] CDH13 cadherin 13 Violent behavior Tiihonen et al. [2015] CHRM2 cholinergic receptor, muscarinic 2 Externalizing behavior Dick et al. [2008]; Dick et al. [2011]; Latendresse et al. [2011] COMT catechol-O-methyltransferase Aggression, externalizing and anger Albaugh et al. [2010]; Calati et al. [2011]; Flory et al. [2007]; Hirata et al. [2013]; Kang et al. [2008]; Kulikova et al. [2008]; Perroud et al. [2010]; Rujescu et al. [2003]; Shehzad et al. [2012] CRHR1 corticotropin releasing hormone receptor 1 Aggressive behavior Chen et al. [2014] CYP17 cytochrome P450, family 17, subfamily A, — Miodovnik et al. [2012] polypeptide 1 CYP19 cytochrome P450, family 19, subfamily A, Externalizing behavior Miodovnik et al. [2012] polypeptide 1 CYP1B1 cytochrome P450, family 1, subfamily B, — Miodovnik et al. [2012] polypeptide 1 DARPP32 protein phosphatase 1, regulatory Anger Reuter et al. [2009] (inhibitor) subunit 1B DBH dopamine beta-hydroxylase (dopamine Aggressive hostility, impulsivity and Hess et al. [2009] beta-monooxygenase) neuroticism DRD2 dopamine receptor D2 Aggressive behavior and violent Chen et al. [2005]; Guo et al. [2007]; Zai delinquency et al. [2012a] DRD3 dopamine receptor D3 Impulsivity in violent offenders Retz et al. [2003] DRD4 dopamine receptor D4 Aggression, aggressive behavior, Boutwell and Beaver [2008];Buchmann externalizing behavior and delinquency et al. [2014]; Dmitrieva et al. [2011]; Farbiash et al. [2014]; Hohmann et al. [2009]; Kang et al. [2008]; Marsman et al. [2013]; Nobile et al. [2007]; Schlomer et al. [2015]; Zai et al. [2012a] ESR1 estrogen receptor 1 Anger Vermeersch et al. [2013] FKBP5 FK506 binding protein 5 Aggressive and violent behavior Bevilacqua et al. [2012] GABRA2 gamma-aminobutyric acid (GABA) A Externalizing behavior Dick et al. [2009] receptor, alpha 2 HTR1A 5-hydroxytryptamine (serotonin) receptor — Keltikangas-Jarvinen et al. [2008]; Serretti 1A, G protein-coupled et al. [2007] HTR1B 5-hydroxytryptamine (serotonin) receptor Aggressive behavior, anger and hostility Conner et al. [2010]; Hakulinen et al. 1B, G protein-coupled [2013]; Zouk et al. [2007] HTR2A 5-hydroxytryptamine (serotonin) receptor Aggression, anger, hostility and criminality Banlaki et al. [2015]; Berggard et al. 2A, G protein-coupled [2003]; Dijkstra et al. [2013]; Giegling et al. [2006]; Keltikangas-Jarvinen et al. [2008]; Mik et al. [2007] HTR2C 5-hydroxytryptamine (serotonin) receptor — Serretti et al. [2007] 2C, G protein-coupled MAOA monoamine oxidase A Aggression, anger, externalizing behavior, Antypa et al. [2013]; Armstrong et al. impulsivity, hostility, use of weapons, [2014]; Beaver and Holtfreter [2009]; delinquent, violent and criminal Beaver et al. [2010a]; Beaver et al. behaviors. [2010b]; Beaver et al. [2014]; Edwards et al. [2010]; Eisenberger et al. [2007]; Frazzetto et al. [2007]; Gallardo-Pujol et al. [2013];Gorodetsky et al. [2014]; (Continued) 680 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

TABLE I. (Continued) References (positive and negative Gene symbol Gene name Associated phenotype associations)

Guo et al. [2008]; Huizinga et al. [2006]; Kuepper et al. [2013]; Manuck et al. [2000, 2002]; Perroud et al. [2010]; Pickles et al. [2013]; Pingault et al. [2013]; Reif et al. [2007]; Sjoberg et al. [2007]; Tiihonen et al. [2015]; van der Vegt et al. [2009]; Verhoeven et al. [2012]; Weder et al. [2009]; Yang et al. [2007] NOS1 nitric oxide synthase 1 (neuronal) Impulsive aggressivity and aggression Reif et al. [2009]; Retz et al. [2010]; Rujescu et al. [2008] NOS3 nitric oxide synthase 3 (endothelial cell) Aggressive behavior Rujescu et al. [2008] OXTR oxytocin receptor Aggression Malik et al. [2012, 2014] SLC6A4 (5HTT) solute carrier family 6 (neurotransmitter Aggression, anger, impulsive aggressivity, Aslund et al. [2013]; Baca-Garcia et al. transporter), member 4 (serotonin hostility, neuroticism, externalizing [2004]; Beitchman et al. [2006]; transporter) behavior, violence, delinquency and Cadoret et al. [2003]; Conway et al. criminality [2012]; Davidge et al. [2004]; Gerra et al. [2005]; Gonda et al. [2009]; Greenberg et al. [2000]; Gyurak et al. [2013]; Haberstick et al. [2006]; Hohmann et al. [2009]; Liao et al. [2004]; Lopez-Castroman et al. [2014]; Nobile et al. [2007]; Perroud et al. [2010]; Reif et al. [2007]; Retz et al. [2004]; Sysoeva et al. [2009]; Terracciano et al. [2009]; Verona et al. [2006]; Yang et al. [2010]; Zalsman et al. [2001]; Zimmermann et al. [2009] SLC6A3 (DAT1) solute carrier family 6 (neurotransmitter Externalizing behavior, pathological Beaver et al. [2008]; Chen et al. [2005]; transporter), member 3 (dopamine violence, serious delinquency and Guo et al. [2007]; Young et al. [2002]; transporter) criminal conduct Zai et al. [2012a] SLIT2 slit homolog 2 (Drosophila) Anger Sokolowski et al. [2010] TBX19 T-box 19 Angry hostility Wasserman et al. [2007] TH tyrosine hydroxylase Angry hostility and neuroticism (Persson et al. [2000] TPH1 tryptophan hydroxylase 1 Aggression, aggressive behavior, anger and Evans et al. [2000]; Hennig et al. [2005]; violence Manuck et al. [1999]; Reuter and Hennig [2005]; Perroud et al. [2010]; Rotondo et al. [1999]; Rujescu et al. [2002]; Yang et al. [2010] TPH2 tryptophan hydroxylase 2 Anger Mann et al. [2008]; Yang et al. [2010]; Yoon et al. [2012]

adverse environmental factors (e.g., maltreatment, childhood Prom-Wormley et al., 2009; Qian et al., 2009; Derringer et al., 2010; trauma, social exclusion) contributing to the occurrence of aggres- Wakschlag et al., 2010; Fergusson et al., 2011; McGrath et al., 2012; sive behaviors such as aggression, violent behavior, criminal and Kieling et al., 2013]. The low activity alleles have also been found delinquent behavior and anger proneness [Frazzetto et al., 2007; associated with ASPD and antisocial behavior [Nilsson et al., 2006; Reif et al., 2007; Weder et al., 2009; Beaver et al., 2010b; Edwards Williams et al., 2009; Beach et al., 2010; Reti et al., 2011], and also in et al., 2010; Gallardo-Pujol et al., 2013; Pickles et al., 2013; the presence of adverse environments (e.g., sexual assault, abuse, Armstrong et al., 2014; Gorodetsky et al., 2014]. These findings maltreatment) in GxE studies [Caspi et al., 2002; Derringer et al., are consistent, since only a few studies have failed to replicate the 2010; Cicchetti et al., 2012; Fergusson et al., 2012]. However, some results or have identified high activity alleles associated with studies did not replicate those results in antisocial behavior aggressive behaviors, some of them performed only in females [Widom and Brzustowicz, 2006; Prichard et al., 2007; Haberstick [Huizinga et al., 2006; Sjoberg et al., 2007; Yang et al., 2007; Beaver et al., 2014]. Psychopathy seems to be also associated with MAOA and Holtfreter, 2009; van der Vegt et al., 2009; Perroud et al., 2010; low activity alleles, and in some cases in the presence of children Verhoeven et al., 2012]. Studies evaluating the MAOA uVNTR in maltreatment [Kim-Cohen et al., 2006; Fowler et al., 2009; Sadeh ODD and CD only identified associations with CD and conduct et al., 2013]. Recent meta-analyses have evaluated the contribution problems in the presence of adverse childhood environments of the MAOA uVNTR to aggressive behavior with positive results. [Foley et al., 2004; Haberstick et al., 2005; Young et al., 2006; Ficks and Waldman [2014] identified association between the low FERNANDEZ-CASTILLO AND CORMAND 681

TABLE II. Candidate Genes Investigated in CD, ODD, CU, Antisocial Behavior and Psychopathy

References (positive and negative Gene symbol Gene name Associated phenotype associations) AR androgen receptor Antisocial behavior Prichard et al. [2007] AVPR1A arginine vasopressin receptor 1A — Prichard et al. [2007] BDNF brain-derived neurotrophic factor ODD, CU and psychopathy Kourmouli et al. [2013]; Willoughby et al. [2013] COMT catechol-O-methyltransferase CD Caspi et al. [2008]; DeYoung et al. [2010]; Fowler et al. [2009]; Qian et al. [2009] DBH dopamine beta-hydroxylase (dopamine — Prichard et al. [2007] beta-monooxygenase) DRD2 dopamine receptor D2 — Beaver et al. [2007]; Prichard et al. [2007] DRD4 dopamine receptor D4 CD, ODD and CU Beaver et al. [2007]; Kirley et al. [2004]; Martel et al. [2011]; Nikitopoulos et al. [2014]; Zohsel et al. [2014] ESR1 estrogen receptor 1 Antisocial behavior, neuroticism and Prichard et al. [2007]; Westberg et al. psychoticism [2003] HTR1B 5-hydroxytryptamine (serotonin) CD Jensen et al. [2009]; Moul et al. [2013]; receptor 1B, G protein-coupled Wang et al. [2012] HTR2A 5-hydroxytryptamine (serotonin) CU and antisocial behavior (Burt and Mikolajewski [2008]; Moul receptor 2A, G protein-coupled et al. [2013] MAOA monoamine oxidase A CD and ODD with adverse childhood Beach et al. [2010]; Byrd and Manuck, environment, Antisocial behavior, 2014]; Caspi et al. [2002]; Cicchetti ASPD, conduct problems and et al. [2012]; Derringer et al. [2010]; psychopathy Fergusson et al. [2012]; Fergusson et al. [2011]; Foley et al. [2004]; Fowler et al. [2009]; Haberstick et al. [2005]; Haberstick et al. [2014]; Kieling et al. [2013]; Kim-Cohen et al. [2006]; McGrath et al. [2012]; Nilsson et al. [2006]; Philibert et al. [2011]; Prichard et al. [2007]; Prom-Wormley et al. [2009]; Qian et al. [2009]; Reti et al. [2011]; Sadeh et al. [2013]; Wakschlag et al. [2010]; Williams et al. [2009]; Young et al. [2006]; Widom and Brzustowicz [2006] NR4A2 nuclear receptor subfamily 4, group A, Antisocial behavior Prichard et al. [2007] member 2 OXTR oxytocin receptor CD and CU Beitchman et al. [2012]; Dadds et al. [2014]; Malik et al. [2012]; Prichard et al. [2007]; Sakai et al. [2012]; Smearman et al. [2015] SLC6A4 (5HTT) solute carrier family 6 (neurotransmitter CD, conduct problems, antisocial Brody et al. [2011]; Cicchetti et al. transporter), member 4 (serotonin behavior and psychopathy [2012]; Ficks and Waldman [2014]; transporter) Fowler et al. [2009]; Garcia et al. [2010]; Malmberg et al. [2008]; Sadeh et al. [2013]; Sakai et al. [2006, 2007, 2010] SLC6A3 (DAT1) solute carrier family 6 (neurotransmitter ODD and conduct problems Burt and Mikolajewski [2008]; Jorm et al. transporter), member 3 (dopamine [2001]; Lee et al. [2007] transporter) SNAP25 synaptosomal-associated protein, 25kDa Antisocial personality disorder Basoglu et al. [2011] TFAP2B transcription factor AP-2 beta (activating Antisocial behavior Prichard et al. [2007] enhancer binding protein 2 beta) TPH1 tryptophan hydroxylase 1 — Cicchetti et al. [2012] TPH2 tryptophan hydroxylase 2 — Burt and Mikolajewski [2008]

CD, conduct disorder; ODD, oppositional defiant disorder; CU, callous-unemotional; ASPD, antisocial personality disorder. 682 AMERICAN JOURNAL OF MEDICAL GENETICS PART B activity alleles of this polymorphism and antisocial behavior (P Haberstick et al., 2006; Verona et al., 2006; Reif et al., 2007; Gonda ¼ 1.37e-06). Also, Byrd and Manuck [2014] found low activity et al., 2009; Sysoeva et al., 2009; Zimmermann et al., 2009; Conway alleles of MAOA uVNTR associated with antisocial behavior in the et al., 2012; Gyurak et al., 2013; Lopez-Castroman et al., 2014]. presence of childhood maltreatment (P ¼ 8e-07). However, other studies report divergent conclusions, associating Additionally, several SNPs in the MAOA gene have been associ- the long (L) variant with some of these phenotypes [Zalsman et al., ated with physical aggression and anger, and another VNTR with a 2001; Cadoret et al., 2003; Beitchman et al., 2006; Nobile et al., 10-bp repeat unit and also located in the promoter region was 2007; Aslund et al., 2013] or not finding significant associations associated with ASPD in the presence of childhood abuse [Philibert with 5-HTTLPR at all [Baca-Garcia et al., 2004; Davidge et al., 2004; et al., 2011; Antypa et al., 2013; Pingault et al., 2013]. In contrast, no Terracciano et al., 2009; Perroud et al., 2010; Yang et al., 2010]. The association with aggression has been detected for the MAOB gene, S variant was also found associated with conduct problems and CD encoding monoamine oxidase B, with more restrictive substrates [Sakai et al., 2006, 2010; Malmberg et al., 2008; Brody et al., 2011], than monoamine oxidase A [Antypa et al., 2013]. although another study failed to detect significant results [Sakai The COMT gene encodes catechol-o-methyltransferase, in- et al., 2007]. Studies evaluating antisocial behavior also identified volved in the metabolism of dopamine, epinephrine and norepi- association with the S allele [Garcia et al., 2010; Cicchetti et al., nephrine. The Val/Val genotype of the common variation p. 2012], and in a recent meta-analysis the short allele of 5-HTTLPR Val158Met (rs4680G>A) has been associated with aggression, was significantly associated with antisocial behavior [Ficks and externalizing behavior and anger in several studies, in one of Waldman, 2014]. In contrast, in the case of psychopathy the them influenced by sexual abuse [Kulikova et al., 2008; Perroud associated allele is the longer variant [Fowler et al., 2009; Sadeh et al., 2010; Shehzad et al., 2012]. However, other studies failed to et al., 2013]. Also, a 12-bp VNTR in intron 2 of the 5HTT gene has replicate these results or found the Met allele associated with anger been found associated with aggression and antisocial behavior and aggressive behavior [Rujescu et al., 2003; Flory et al., 2007; [Davidge et al., 2004; Garcia et al., 2010]. Kang et al., 2008; Albaugh et al., 2010]. The Val allele and the Val/ Regarding serotonin receptors, several SNPs in the HTR2A gene Val genotype have been associated with CD and ODD [Caspi et al., associate with aggression, criminality, hostility and anger [Berg- 2008; DeYoung et al., 2010; Qian et al., 2009], but not with total gard et al., 2003; Giegling et al., 2006; Mik et al., 2007; Keltikangas- psychopathy scores, only with emotional dysfunction [Fowler Jarvinen et al., 2008; Dijkstra et al., 2013; Banlaki et al., 2015] and et al., 2009]. Other polymorphisms in the COMT gene have also also with CU and antisocial behavior [Burt and Mikolajewski, 2008; been associated with aggression and anger reactions [Calati et al., Moul et al., 2013]. Variants and haplotypes in the HTR1B gene have 2011; Hirata et al., 2013], and an epistatic interaction of COMT, been associated with aggressive behavior, anger and hostility [Zouk TPH, and HTR2A genes was found with ASPD [Cuartas Arias et al., et al., 2007; Conner et al., 2010; Hakulinen et al., 2013] and also 2011]. with CD and CU, but not with ASPD [Jensen et al., 2009; Wang Other less studied genes encoding enzymes involved in the et al., 2012; Moul et al., 2013]. However, Perroud et al. did not synthesis or degradation of serotonin and dopamine are TPH1, observe significant associations between HTR2A and HTR1B var- TPH2, DBH, and TH. No consistent results have been observed for iants and anger [Perroud et al., 2010]. In contrast with those genes, the TPH1 gene [Manuck et al., 1999; Rotondo et al., 1999; Evans no associations were identified for HTR1A and HTR2C [Serretti et al., 2000; Rujescu et al., 2002; Hennig et al., 2005; Reuter and et al., 2007; Keltikangas-Jarvinen et al., 2008]. Hennig, 2005; Perroud et al., 2010; Yang et al., 2010; Cicchetti et al., The dopamine transporter is encoded by the SLC6A3 gene (or 2012] nor for TPH2 [Burt and Mikolajewski, 2008; Mann et al., DAT1). A 40bp VNTR located in the 3’UTR region has been 2008; Perroud et al., 2010; Yang et al., 2010; Yoon et al., 2012]. One associated with criminal conduct, pathological violence and violent study identified association of a functional SNP (rs1611115) in the delinquency, the 10-repeat allele (10R) being the risk factor [Chen promoter region of the DBH gene with aggressive hostility and et al., 2005; Guo et al., 2007; Beaver et al., 2008], although 9R was impulsivity, whereas another one investigated a dinucleotide repeat the risk allele for externalizing behavior [Young et al., 2002]. (TG) also in the promoter region of this gene but did not detect However, another study did not succeed in identifying association association with antisocial behavior [Hess et al., 2009; Prichard with aggression [Zai et al., 2012a]. This VNTR polymorphism was et al., 2007]. Another repeat (TCAT) located in the first intron of also associated with ODD and antisocial behavior, but not with CD the TH gene was found associated with angry hostility [Persson [Jorm et al., 2001; Lee et al., 2007; Burt and Mikolajewski, 2008]. et al., 2000]. Another dopaminergic gene, DRD4, encoding the dopamine The serotonin transporter is encoded by the SLC6A4 gene, also receptor D4, has been associated with several aggression pheno- known as 5HTT. A functional polymorphism in the promoter types. The 7-repeat allele of a 48bp VNTR in exon 3 of the gene is region, called 5-HTTLPR (Serotonin-Transporter-Linked Poly- associated with aggression, aggressive behavior, delinquency, ex- morphic Region) has been associated with aggressive behavior. ternalizing behavior [Nobile et al., 2007; Boutwell and Beaver, It consists of a degenerate repeat with more than 10 variants, 2008; Hohmann et al., 2009; Dmitrieva et al., 2011; Buchmann although researchers usually report only two, the short (S) and the et al., 2014; Farbiash et al., 2014; Schlomer et al., 2015] and with long (L) alleles. The short variant (S), driving lower transcription ODD and CD [Kirley et al., 2004; Nikitopoulos et al., 2014; Zohsel levels, and the SS genotype, have been found associated with et al., 2014]. Others found association between the 4-repeat allele aggressive behavior, aggression, anger, hostility, impulsive aggres- and externalizing behavior and anger [Kang et al., 2008; Marsman sivity, neuroticism, violent behavior and criminality [Greenberg et al., 2013], whereas Zai et al. [2012a] did not observe a significant et al., 2000; Liao et al., 2004; Retz et al., 2004; Gerra et al., 2005; association between this VNTR and aggression. Another polymor- FERNANDEZ-CASTILLO AND CORMAND 683 phism in the promoter region (a 120-bp repeat) was associated with encoding the corticotropin releasing hormone receptor 1 (CRHR1) ODD in the presence of inconsistent parenting [Martel et al., 2011]. have been associated with aggressive behavior [Chen et al., 2014]. A The gene for the dopamine receptor 2 (DRD2) has also been study investigated functional polymorphisms in the genes CYP17, associated with violent delinquency and aggressive behavior CYP19, and CYP1B1, which control the major enzymatic steps in [Chen et al., 2005; Guo et al., 2007; Zai et al., 2012a], but not sex steroid synthesis and metabolism, and identified association with antisocial behavior [Prichard et al., 2007]. A study performed between externalizing problems in boys and a functional SNP in the by Beaver et al. did not detect independent associations between the CYP19 gene which affects levels of estradiol and testosterone DRD2 or DRD4 genes and CD or antisocial behavior, but identified (rs10046 in the 30UTR) [Miodovnik et al., 2012]. Several SNPs an interaction between both genes that predicted both phenotypes in the ABCG1 gene, encoding a transporter involved in cholesterol [Beaver et al., 2007]. Also, an epistatic interaction of the S allele of and sterol homeostasis, showed association with aggression and the 5-HTTLPR variation with the 7R allele of the DRD4 VNTR anger [Gietl et al., 2007]. The FKBP5 gene, coding for a chaperone associated with aggressive and delinquent behavior [Hohmann involved in glucocorticoid response, was associated with aggressive et al., 2009]. Another study identified an association between DRD3 and violent behavior in individuals exposed to childhood trauma and impulsivity in violent offenders [Retz et al., 2003]. [Bevilacqua et al., 2012]. Other genes related to dopamine, involved in signaling or in the Other genes. Other candidate genes have been investigated in regulation of transcription of dopaminergic genes, have also been aggressive behaviors (Tables I and II). Thus, genes involved in associated with aggressive behaviors: DARPP32 was associated with neurotransmission, such as those related to acetylcholine (Ach), anger and amygdala volume [Reuter et al., 2009], AP2B with nitric oxide (NO) and GABA, have also been found associated aggression [Damberg et al., 2000], and NR4A2 and TFAP2B with aggression. The CHRM2 gene, encoding the cholinergic with antisocial behavior in women [Prichard et al., 2007]. muscarinic receptor 2, was associated with externalizing behavior Hormone regulation. Since aggressive behaviors are more [Dick et al., 2008, 2011; Latendresse et al., 2011]. Also, variants in frequently found in males than in females, genes involved in the gene cluster of cholinergic nicotinic receptors CHRNA5/ hormone regulation responsible for sex differences and gender- CHRNA3/CHRNB4 were found associated with the same pheno- related behaviors have been usual suspects in the study of the type [Stephens et al., 2012]. Regarding the NO neurotransmitter, genetics of aggression. The most studied ones are those involved in polymorphic variants in the NOS1 gene, encoding the nitric oxide steroid hormone regulation (androgen and estrogen receptors) synthase 1, have been associated with aggressive behavior, aggres- and neurohypophysial hormones involved in sexual reproduction, sion and impulsivity in offenders [Rujescu et al., 2008; Reif et al., and gender and social behaviors (vasopressin and its receptors, 2009; Retz et al., 2010], and a NOS3 haplotype displayed associa- and oxytocin receptor) (Tables I and II). tion with increased aggression [Rujescu et al., 2008]. The GABA The androgen receptor is encoded by the AR gene. The shorter receptor encoded by GABRA2 was found associated with high alleles of a trinucleotide repeat in exon 1 were found to be externalizing behavior [Dick et al., 2009]. A common variant in associated with violent criminal behavior and aggression in men the promoter region of the adrenergic alpha 2A receptor gene [Jonsson et al., 2001; Cheng et al., 2006; Rajender et al., 2008]. This (ADRA2A) was found associated with aggression, irritability and polymorphism was also found associated with antisocial behavior hostility [Comings et al., 2000]. [Prichard et al., 2007]. Regarding the ESR1 gene, encoding the Also, genes involved in neuroadaptations have been assessed. estrogen receptor 1, two SNPs and a microsatellite (a TG repeat in Variants in BDNF (brain-derived neurotrophic factor) have been the 50 region) have been associated with anger, neuroticism, associated with aggressive behavior and aggression and impul- indirect aggression and antisocial behavior [Westberg et al., sivity, but not with anger [Perroud et al., 2010; Kretschmer et al., 2003; Prichard et al., 2007; Vermeersch et al., 2013]. 2014; Musci et al., 2014]. A BDNF SNP (rs6265, p.Val66Met) was Variants in genes coding for vasopressin and its receptors (AVP, also associated with ODD and CU, and psychopathology, but the AVPR1A and AVPR1B) have been reported to be associated with identity of the risk allele is not consistent across studies aggression. Two SNPs in the AVP and AVPR1A genes were [Kourmouli et al., 2013; Willoughby et al., 2013]. Sokolowski associated with pervasive aggression only in males, whereas a et al. investigated 14 genes involved in axonal guidance and microsatellite (RS1) in the promoter region of AVPR1A was identified an association of anger with SLIT2 [Sokolowski et al., associated with aggression and anger [Malik et al., 2014; Moons 2010], which has been shown to determine dopaminergic and et al., 2014]. An association identified between reactive aggression serotonergic circuits in the forebrain [Bagri et al., 2002; Lin et al., and the SNP rs35369693 in the AVPR1B gene was replicated by 2005]. A SNP in the gene encoding the A-kinase-anchoring other authors in the same phenotype [Zai et al., 2012b; Luppino protein 5 (AKAP5), a post-synaptic multi-adaptor molecule, et al., 2014]. Two microsatellites repeats in the AVPR1A genes were was found associated with aggressive behavior and anger [Richter studied, but no association was found with antisocial behavior et al., 2011]. The ankyrin 3 gene (ANK3),whichisinvolvedin [Prichard et al., 2007]. SNPs in the oxitocin receptor gene (OXTR) neuronal activity, showed association with externalizing behavior have been associated with aggression [Malik et al., 2012, 2014], and [Logue et al., 2013]. The synaptosomal-associated protein 25 also with conduct problems and CD [Sakai et al., 2012; Smearman gene (SNAP25), related to neurotransmitter release, was found et al., 2015], as well as CU [Beitchman et al., 2012; Dadds et al., associated with antisocial personality disorder [Basoglu et al., 2014]. However, two studies did not identify associations between 2011]. CDH13, encoding cadherin 13, a neuronal membrane variants in this gene and antisocial behavior or CU [Prichard et al., adhesion protein, showed association with extremely violent 2007; Malik et al., 2012]. A SNP and a haplotype in the gene behavior [Tiihonen et al., 2015]. 684 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

Finally, another study identified association between angry A meta-analysis of ADHD GWAS data showed that polygenic and hostility and the gene TBX19, encoding the hypothalamic- risk for ADHD was higher in ADHD with CD, and that it was pituitary-adrenocortical axis regulatory factor [Wasserman et al., mainly associated with aggression [Hamshere et al., 2013]. 2007]. In another GWAS, Tielbeek et al. [2012] assessed antisocial behavior in adults using a self-report questionnaire. The top signal DYRK1A Genome-Wide Association Studies from that GWAS implicated (with 30 SNPs showing p- values <10e-5). DYRK1A encodes a kinase with a role in synaptic Only a few association studies of aggression have been performed plasticity and brain development. using hypothesis-free approaches through GWAS. Although none Finally, Viding et al. [2010] performed a two-stage GWAS on of them identified genome-wide significant findings, we will dis- psychopathic tendencies in children (antisocial behavior combined cuss a number of suggestive associations. These studies have with CU), identifying several suggestive associations that were allowed the identification of genes involved in aggressive behavior nominally replicated. Some of the top 30-ranked SNPs that showed that had not been considered in any previous GCAS. Interestingly, association with psychopathic traits were located in neurodeve- several of them are involved in synaptic plasticity. lopmental genes, such as ROBO2 [Viding et al., 2010]. One of the Mick et al. performed two GWAS on aggressive traits. The first genes within the top 30-ranked is the serotonin receptor HTR1B, one assessed the Child Behavior Checklist Dysregulation Profile which had previously been associated with CU traits, CD, child- (CBCL-DP), including three different clinical subscales (aggressive hood aggressive behavior, impulsive aggression, anger and hostility behavior, anxiety/depression, attention problems), on ADHD [Zouk et al., 2007; Jensen et al., 2009; Conner et al., 2010; affected family trios [Mick et al., 2011]. CBCL-DL elevated scores Hakulinen et al., 2013; Moul et al., 2013]. increase susceptibility to aggressive behavior and psychopathology. Increased aggressive behavior scores were found nominally associ- ated with several genes, including LRRC7, STIP1 and TMEM132D. Pathways and Functions Involved in Aggression These three genes are involved in neuronal excitability, astrocyte We investigated whether any pathways or functions were over- differentiation and anxiety-related behaviors, respectively. The represented across the different GWAS performed on aggressive second GWAS reported investigated proneness to anger by assess- behaviors. Six GWAS were considered for the analyses, three per- ing measures of angry temperament and angry reaction [Mick et al., formed in children [Anney et al., 2008; Viding et al., 2010; Mick et al., 2014]. A nominal association was found between anger and the 2011],oneinadolescentsandyoungadults[Merjonenetal.,2011]and FYN gene, involved in calcium influx and release in the post- two in adults [Tielbeek et al., 2012; Mick et al., 2014]. A total of 559 synaptic density and also in long-term potentiation. The long-term signals from these six GWAS, selected for its statistical significance, potentiation pathway could play a role in aggressive behavior both were located close to 156 genes (see methods described under in children and in adults, since FYN, LRRC7 and STIP1, identified Literature Searches and Bioinformatic Analyses, Figure 1 and Sup- in this GWAS, as well as other nominally associated genes in the plementary Tables SI and SII). Interestingly, the A2BP1 and NFKB1 previous one, such as BDNF, NTRK2 and CAMK2A, are mediators genes were identified in two different GWAS (Fig. 1). in this pathway [Mick et al., 2011, 2014]. The results of the bioinformatic analyses performed on these In a third GWAS, Merjonen et al. [2011] assessed hostility in 156 genes (Supplementary Table SII) highlighted relevant pathways adolescents and in adult males, considering three dimensions: and functions. KEGG pathways analyses revealed “axon guidance” as anger, cynicism and paranoia. They identified several SNPs show- the most significantly enriched pathway (rawP ¼ 1e-04, adjP ¼ 4e-03; ing nominal associations with anger, several of them located in the Table III, Fig. 2), with five genes represented in all cases, converging to PURG and SHISA6 genes. However, little is known about the actual axon repulsion signaling. Interestingly, the SLIT2 gene associated with function of the encoded proteins [Merjonen et al., 2011]. anger in a CGAS study mentioned above [Sokolowski et al., 2010] enc- Anney et al. [2008] performed a family-based genome-wide study ] encodes a protein that is a ligand for ROBO2, found associated with considering three measures of conduct problems. They identified nine psychopathic traits in the GWAS of Viding et al. [2010] and replicated genes nominally associated with conduct problems considering the by Dadds et al. [2013] (Fig. 2). Other interesting enriched KEGG dominant, recessive or additive models: A2BP1, c12orf28, FLJ39061, pathways identified were “Neuroactive ligand-receptor interaction” KIRREL3, LOC729257, PAWR, PKD1L2, PKD1L3 and RGL1. A2BP1 and “MAPK signaling pathway” (Table III). The most remarkable and KIRREL3 encode proteins involved in neuron development and Common pathway identified is “plasma membrane estrogen receptor synaptic plasticity, respectively, and PAWR participates in the regula- signaling”, involving 10 genes associated with aggressive behavior in tion of dopamine receptor D2 signaling. However, little is known the different GWAS reports (Table III), which highlights the impor- about the function of the other genes in the brain. tance of hormone regulation in aggressive behaviors. GO analyses Another GWAS studied the interaction between genes and envi- revealed several enriched functions such as neuron projection (den- ronmental risk factors (GxE) [Sonuga-Barke et al., 2008], and found drite, neuron spine and axon part), cell junction and ion gated channel nominal associations between CD and mother’s warmth interacting activity, although none of them survived corrections for multiple with several variants in five genes: RIT1, ADH1C, SLC6A1, A2BP1, testing. The most interesting functions identified with Diseases and and MFHAS1. The SLC6A1 gene codes for a GABA transporter, and Bio Functions analyses were “formation of the forebrain”, involving the proteins encoded by RIT1 and A2BP1 are involved in neuronal seven genes (ALDH1A2, BMP2, FYN, GSK3B, PTPRS, ROBO2,and development and regeneration. Interestingly, A2BP1 was also asso- SEMA3A) and “development of neurons”, involving 18 genes (ALK, ciated with CD in the GWAS discussed above [Anney et al., 2008]. ATOH1, BMP2, CACNB2, DLG5, DYRK1A, FMN1, FYN, GSK3B, FERN

TABLE III. Pathways and Functions Enriched With Genes Found Associated With Aggressive Behaviors in GWAS Studies NE-ATLOADCORMAND AND ANDEZ-CASTILLO Gene symbol Other aliases Gene name EntrezGene ID Ensembl ID Phenotype GWAS study

Axon Guidance KEGG pathway ID: 04360 C ¼ 129; O ¼ 5; E ¼ 0.47; R ¼ 10.72; rawP ¼ 0.0001; adjP ¼ 0.0041

GSK3B — glycogen synthase kinase 3 beta 2932 ENSG00000082701 Anger Merjonen et al. [2011] Y SLK,FYN SYN, p59-FYN FYN oncogene related to SRC, 2534 ENSG00000010810 Anger Mick et al. [2014] FGR, YES ROBO2 SAX3 roundabout, axon guidance 6092 ENSG00000185008 ABþ/CUþ Viding et al. [2010] receptor, homolog 2 (Drosophila) SEMA3A COLL1, HH16, Hsema-I, Hsema-III, sema domain, immunoglobulin 10371 ENSG00000075213 CBCL-DP Mick et al. [2011] domain (Ig), short basic domain, secreted, (semaphorin) 3A SEMA1, SEMAD, SEMAIII, SEMAL, SEMA4B SEMAC, SemC sema domain, immunoglobulin 10509 ENSG00000185033 antisocial behavior Tielbeek et al. [2012] SemD, coll-1 domain (Ig), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4B

Neuroactive ligand- KEGG pathway ID: 04080 C ¼ 272; O ¼ 5; E ¼ 0.98; receptor interaction R ¼ 5.08; rawP ¼ 0.0032; adjP ¼ 0.0127 GABRB1 — gamma-aminobutyric acid (GABA) 2560 ENSG00000163288 Anger Merjonen et al. [2011] A receptor, beta 1 PTGDR AS1, ASRT1, DP, DP11,PTGDR prostaglandin D2 receptor (DP) 5729 ENSG00000168229 Anger Mick et al. [2014] GLRA3 — glycine receptor, alpha 3 8001 ENSG00000145451 CBCL-DP Mick et al. [2011] E RCD295,LEPR LEP-RD, OB-R, OBR, LEPR leptin receptor 3953 ENSG00000116678 ABþ/CUþ Viding et al. [2010] PRSS2 TRY2, TRY8, TRYP2 protease, serine, 2 (trypsin 2) 5645 NA antisocial behavior Tielbeek et al. [2012]

MAPK signaling pathway KEGG pathway ID: 04010 C ¼ 268; O ¼ 5; E ¼ 0.97; R ¼ 5.16; rawP ¼ 0.0030; adjP ¼ 0.0127 FGF14 FGF-14, FHF-4, FHF4, SCA27 fibroblast growth factor 14 2259 ENSG00000102466 CBCL-DP Mick et al. [2011] RAPGEF2 CNrasGEF, NRAPGEP, PDZ-GEF1, Rap guanine nucleotide exchange 9693 ENSG00000109756 antisocial behavior Tielbeek et al. [2012] factor (GEF) 2

CACNB2 CACNLB2, CAVB2, MYSB calcium channel, voltage- 783 ENSG00000165995 CBCL-DP Mick et al. [2011] PDZGEF1, RA-GEF, RA-GEF-1, dependent, beta 2 subunit NFKB1 EBP-1,Rap-GEP, KBF1, NF-kB1, nRap GEP NF-kappa-B, nuclear factor of kappa light 4790 ENSG00000109320 Anger and antisocial Mick et al. [2014] NF-kappaB, NFKB-p105, NFKB- polypeptide gene enhancer in behavior and Tielbeek et al. [2012] p50, NFkappaB, p105, p50 B-cells 1 PLA2G4E — phospholipase A2, group IVE 123745 ENSG00000188089 Anger Merjonen et al. [2011]

Ligand-gated ion cannel Pathway Commons ID: 985 C ¼ 17; O ¼ 3; E ¼ 0.06; transport R ¼ 48.79; rawP ¼ 3.04e-05; adjP ¼ 0.0022 685 (Continued) 686 TABLE III. (Continued) Gene symbol Other aliases Gene name EntrezGene ID Ensembl ID Phenotype GWAS study

GABRB1 — gamma-aminobutyric acid (GABA) 2560 ENSG00000163288 Anger Merjonen et al. [2011] A receptor, beta 1 HTR3E 5-HT3-E, 5-HT3E, 5-HT3c1 5-hydroxytryptamine (serotonin) 285242 ENSG00000186038 Anger Merjonen et al. [2011] receptor 3E, ionotropic GLRA3 — glycine receptor, alpha 3 8001 ENSG00000145451 CBCL-DP Mick et al. [2011]

Neuronal system Pathway Commons ID: 143 C ¼ 188; O ¼ 5; E ¼ 0.68; R ¼ 7.35; rawP ¼ 0.0006; adjP ¼ 0.0144 KCNQ4 DFNA2, DFNA2A, KV7.4 potassium voltage-gated channel, 9132 ENSG00000117013 Anger Mick et al. [2014] KQT-like subfamily, member 4 SLC22A2 OCT2 solute carrier family 22 (organic 6582 ENSG00000112499 Anger Mick et al. [2014] cation transporter), member 2 GABRB1 — gamma-aminobutyric acid (GABA) 2560 ENSG00000163288 Anger Merjonen et al. [2011] A receptor, beta 1 KCND3 KCND3LS, KSHIVB, KV4.3, SCA19, potassium voltage-gated channel, 3752 ENSG00000171385 ABþ/CUþ Viding et al. [2010] SCA22,KCND3 Shal-related subfamily, member 3 ABAT GABA-AT, GABAT, NPD009 4-aminobutyrate 18 ENSG00000183044 Anger Mick et al. [2014] aminotransferase

Plasma membrane Pathway Commons ID: 1556 C ¼ 1301; O ¼ 10; E ¼ 4.71; estrogen receptor R ¼ 2.12; rawP ¼ 0.0203; signaling adjP ¼ 0.0400 M 2BDA2A,BMP2 BMP2 bone morphogenetic protein 2 650 ENSG00000125845 Anger Merjonen et al. [2011] Y SLK,FYN SYN, p59-FYN FYN oncogene related to SRC, 2534 ENSG00000010810 Anger Mick et al. [2014] FGR, YES ZAP70 SRK, STCD, STD, TZK, ZAP-70 zeta-chain (TCR) associated 7535 ENSG00000115085 CBCL-DP Mick et al. [2011] protein kinase 70kDa NFKB1 EBP-1, KBF1, NF-kB1, NF-kappa-B, nuclear factor of kappa light 4790 ENSG00000109320 Anger and antisocial Mick et al. [2014] polypeptide gene enhancer in behavior and Tielbeek et al. [2012] NF-kappaB, NFKB-p105, NFKB- GENETICS MEDICAL OF JOURNAL AMERICAN p50, NFkappaB, p105, p50 B-cells 1 CSE1L CAS, CSE1, XPO2 CSE1 chromosome segregation 1- 1434 ENSG00000124207 Anger Mick et al. [2014] like (yeast) I K RIP,RIPK1 RIP1 receptor (TNFRSF)-interacting 8737 ENSG00000137275 Anger Mick et al. [2014] serine-threonine kinase 1 GSK3B — glycogen synthase kinase 3 beta 2932 ENSG00000082701 Anger Merjonen et al. [2011] N P NIP3BNIP3 BCL2/adenovirus E1B 19kDa 664 ENSG00000176171 ABþ/CUþ Viding et al. [2010] interacting protein 3 JMJD2C KDM4C, GASC1, JHDM3C, lysine (K)-specific demethylase 23081 ENSG00000107077 CBCL-DP Mick et al. [2011] TDRD14C 4C EXOC6 EXOC6A, SEC15, SEC15L, exocyst complex component 6 54536 ENSG00000138190 CBCL-DP Mick et al. [2011]

GWAS, Genome wide association study; CD, conduct disorder; ABþ/CUþ, antisocial behavior and callous unemotional; CBCL-DP, children behavior checklist yysregulation profile; NA, not available. ¼ ¼ Genes found associated in two GWAS;SEC15L1,the same SEC15L3, genes Sec15pare also in the enriched pathway “Nectin adhesion” from Pathway commons (ID:1472, rawP 0.0198; adjP 0.04). In bold, official gene symbol. ATB PART FERNANDEZ-CASTILLO AND CORMAND 687

FIG. 2. Axon guidance in aggressive behavior. Axon guidance pathway enriched in genes found associated in different GWAS (rawP ¼ 1e-04, adjP ¼ 4e-03). Colored nodes show genes associated with aggression phenotypes in any of the GWAS. Key: Yellow, association with psychopathic tendencies [Viding et al., 2010]; orange and red with anger [Merjonen et al., 2011; Mick et al., 2014, respectively]; green with CBCL scores [Mick et al., 2011]; blue with antisocial behavior [Tielbeek et al., 2012]. () indicates a gene associated with anger in a CGAS study [Sokolowski et al., 2010].

LRRC7, NFKB1, PRSS12, RAPGEF2, ROBO2, SEMA3A, SEPT11, Interestingly, signals in the NFKB1 and A2BP1 genes were identi- STIP1,andUBE2V2), 14 of them related to “neuritogenesis“. Finally, fied in different GWAS, which support their role in aggressive we identified a highly scored gene network that is involved in “Cellular behavior predisposition. The NFKB1 gene, present in the network growth and proliferation, cell death and survival, and post-transla- that emerged from the top hits of different GWAS (Fig. 3), was found tional modification” (Fig. 3). Genes such as FYN, NFKB1, STAU1, associatedwithantisocial behavior and angerintwo GWAS [Tielbeek STIP1,andGSK3B are connected to several associated genes in the etal.,2012; Micketal.,2014],andencodestheNuclearfactorofkappa network. Also, the molecular chaperones HSP70 and HSP90 are light polypeptide gene enhancer in B-cells 1, a transcription regulator central nodes in this network, and these heat-shock proteins have involved in axonal regeneration and degeneration [Haenold et al., been reported to play an important role in glucocorticoid response 2014].TheA2BP1(RBFOX1)genewasalsofoundindifferentGWAS, [Grad and Picard, 2007]. Additionally, the associated gene FKBP5, associated with anger and CD [Anney et al., 2008; Merjonen et al., mentioned in the GCAS section, encodes a protein that works as a 2011], as well as CD interacting with mother’s warmth [Sonuga- co-chaperone of HSP90 modulating glucocorticoid receptor action Barke et al., 2008]. This gene encodes the RNA binding protein, fox-1 [Bevilacqua et al., 2012]. homolog (C. elegans) 1, a neuron-specific RNA splicing factor that 688 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

FIG. 3. Gene network graphical representation of interaction between genes associated with aggressive behavior in GWAS. Best scored network (score ¼ 56) involved in Cellular growth and proliferation, cell death and survival, and post-translational modification. Colored nodes show genes associated with aggression phenotypes in any of the GWAS. Key: Yellow, associated with psychopathic tendencies [Viding et al., 2010]; orange and red with anger [Merjonen et al., 2011; Mick et al., 2014, respectively]; green with CBCL scores (Mick et al., 2011); blue with antisocial behavior [Tielbeek et al., 2012]; purple with CD [Anney et al., 2008].

regulates the expression of large genetic networks during early Sample size is a major source of both false positive and false neuronal development [Fogel et al., 2012]. negative findings, since a large number of individuals is required to Taken together, all these results highlight the importance of achieve the statistical power needed to detect real associations. The neurodevelopmental and synaptic plasticity genes, as well as hor- lack of genome-wide significant findings in the GWAS and the mone-related genes, in determining the susceptibility to aggressive variable results obtained from many of the GCAS is likely due to behaviors. the small sample sizes of these studies (typically a few hundreds of individuals). Candidate gene association studies have often ren- dered conflicting results, since in several cases associations were Limitations and Considerations identified with different alleles of the same genetic variant or could Several limitations and drawbacks of association studies should be not be replicated in the same phenotype. considered here, some of them common to this type of study design Clinical and etiological heterogeneity is also a major source of and some others relevant to the particular phenotype under study. false results in association studies and may have influenced the FERNANDEZ-CASTILLO AND CORMAND 689 results discussed above. Thus, when assessing aggression-related gene studies have found associations mainly with dopaminergic phenotypes, it may be relevant to subdivide the different pheno- and serotonergic genes (MAOA, 5HTT, HTR1B, HTR2A, DAT, types into more homogeneous groups (e.g., reactive versus proac- DRD2, DRD4) and with hormone-related genes (AR, ESR1, AVP, tive aggression) rather than consider them as a whole, since OXTR), which have historically received most attention. The variability in the causes of each type of aggressive behavior may MAOA, 5HTT, and DRD4 genes (the most studied ones) have dilute genetic susceptibility effects. Also, many association studies consistently been associated with different aggressive behaviors, have been performed in samples of patients with other psychiatric both with aggressive traits and with diagnostic categories. conditions that could explain the aggressive behaviors observed, Regarding genome-wide studies, although none of them such as drug dependence, bipolar disorder or schizophrenia. As achieved genome-wide significance, they have been helpful in these samples may prevent us from identifying aggression-specific highlighting potential risk genes and pathways involved in neuro- associations, in this review we have considered only those data developmental processes, such as neuron projection and synaptic obtained from studies in which aggressive behaviors were the major plasticity, not previously considered in candidate gene studies. outcome or diagnosis. Although these selection criteria do not This may indicate that aggressive behaviors do not only involve guarantee etiological homogeneity, since comorbidities with other neurotransmitters or hormonal functions, but also molecules psychiatric disorders are anyway present in several individuals of involved in establishing neuronal circuits, neuron-to-neuron these samples, heterogeneity is considerably reduced. connectivity and brain plasticity. Signaling pathways seem to Age is an important factor in aggressive behaviors and may also play an important role in these processes, such as those involved influence the results obtained. Although in this report we have in the control of synaptic and neuronal function, as well as discussed all studies without considering the age of the individuals, hormonal signaling. a recent review briefly comments on the same studies separated by To date, results obtained from association studies should be age groups (children, adolescents and adults) [Veroude et al., taken with caution since some results are conflicting and are often 2015]. performed in underpowered samples. Future studies should be On the other hand, the existence of gender differences in performed in larger samples, use homogeneous phenotypes and aggressive behavior is well known, since aggression is more preva- standardized measurements, also combined with neuroimaging lent in males. Several factors may influence this outcome, such as data, to identify genes that underlie aggressive behaviors in hormone effects on brain function, neurobiological differences and humans. gender differences in social roles. Ideally, genetic association studies should consider gender differences and cases and controls should be sex-matched or gender should be used as a covariate. In ACKNOWLEDGMENTS MAOA the case of X-linked genes, like , studies performed only in We wish to thank Eric Mick, P€aivi Merjonen, Jorim Tielbeek and males are quite more reliable than those performed in women or in Richard Anney for kindly providing us with the data from their mixed samples, as discussed above (section 3, under Candidate GWAS studies. Dr. NF-C was supported by the Centro de Inves- Gene Association Studies (CGAS)). tigacion Biomedica en Red de Enfermedades Raras (CIBERER). Cultural differences could also affect the results obtained in Prof. Cormand received financial support from the Spanish “Min- association studies. Violence and criminality indexes show differ- isterio de Economı´a y Competitividad” (SAF2012-33484), AGAUR ences worldwide and can be influenced by laws, economy, moral (2014SGR932) and from the European Community’s Seventh and ethics. Framework Programme (FP7/2007-2013) under grant agreement Aggressive behavior includes different forms of aggression that #602805. This paper reflects only the author’s views and the can involve different emotional states such as to increased anger, European Union is not liable for any use that may be made of decreased fear, high emotional reactivity or decreased control, the information contained therein. among others. Neuroimaging studies can be helpful in quantifying activity of specific brain regions or circuits associated with these different emotions that can trigger aggression. 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