Using the ethical theories of virtue ethics and cultural relativism, critically analyze the ethical issues raised by the research article provided.
Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder Th Att and cite Gra Gra He Sev Gra 602 643 Gra Gr Az. Spa SAF � RESEARCH ARTICLE Neuropsychiatric Genetics Genome-Wide Analyses of Aggressiveness in Attention-Deficit Hyperactivity Disorder Erlend J. Brevik,1,2,3* Marjolein M. J. van Donkelaar,4 Heike Weber,5 Cristina S�anchez-Mora,6,7,8 Christian Jacob,9 Olga Rivero,10 Sarah Kittel-Schneider,10 Iris Garcia-Martı́nez,6,7 Marcel Aebi,11,12 Kimm van Hulzen,4 Bru Cormand,13,14,15 Josep A. Ramos-Quiroga,6,7,8,16 IMAGE Consortium, Klaus-Peter Lesch,9,17 Andreas Reif,5 Marta Ribas�es,6,7,8 Barbara Franke,4,18 Maj-Britt Posserud,1,2 Stefan Johansson,19,20 Astri J. Lundervold,2,3 Jan Haavik,1,2 and Tetyana Zayats2* 1Division of Psychiatry, Haukeland University Hospital, Bergen, Norway 2K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway 3Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway 4Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands 5Department of Psychiatry, Psychosomatics and Psychotherapy, University of Frankfurt, Frankfurt, Germany 6Psychiatric Genetics Unit, Vall d’Hebron Research Institute (VHIR), Universitat Aut�onoma de Barcelona, Barcelona, Spain 7Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain 8Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain 9Department of Psychiatry and Psychotherapy, Klinik N€urtingen, N€urtingen, Germany 10Division of Molecular Psychiatry, Center of Mental Health, University of W€urzburg, W€urzburg, Germany 11Department of Forensic Psychiatry, Child and Youth Forensic Service, University Hospital of Psychiatry, Zurich, Switzerland 12Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland 13Facultat de Biologia, Departament de Gen�etica, Universitat de Barcelona, Catalonia, Spain 14Centro de Investigaci�on Biom�edica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain 15Institut de Biomedicina de la Universitat de Barcelona (IBUB), Catalonia, Spain 16Department of Psychiatry and Legal Medicine, Universitat Aut�onoma de Barcelona, Barcelona, Spain 17Department of Translational Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands 18Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands 19Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway 20Department of Clinical Science, University of Bergen, Bergen, Norway Manuscript Received: 23 June 2015; Manuscript Accepted: 9 February 2016 is is an open access article under the terms of the Creative Commons ribution-NonCommercial License, which permits use, distribution reproduction in any medium, provided the original work is properly d and is not used for commercial purposes. nt sponsor: K.G. Jebsen Foundation for Medical Research; nt sponsor: University of Bergen; Grant sponsor: Western Norwegian alth Authorities (Helse Vest); Grant sponsor: European Community’s enth Framework Programme; Grant number: FP7/2007–2013; nt sponsor: Research and Innovation Program; Grant numbers: 805, H2020; Grant sponsor: Marie Sklodowska-Curie; Grant number: 051 (MiND); Grant sponsor: Deutsche Forschungsgemeinschaft; nt numbers: DFG: KFO 125, TRR 58/A5, DFG RE1632/5-1; ant sponsor: Fritz Thyssen Foundation; Grant number: 10.13.1185; Grant sponsor: Jacobs Foundation; Grant sponsor: nish Ministerio de Economı́a y Competitividad; Grant number: 2012-33484; Grant sponsor: AGAUR; Grant number: 2014SGR932; Grant sponsor: Instituto de Salud Carlos III, Ministerio de Ciencia e Innovaci�on, Spain; Grant sponsor: Instituto de Salud Carlos III-FIS, Spain; Grant numbers: PI11/00571, PI11/01629, PI12/01139, PI14/01700; Grant sponsor: Ag�encia de Gesti�o d’Ajuts Universitaris i de Recerca- AGAUR Generalitat de Catalunya; Grant number: 2014SGR1357; Grant sponsor: Departament de Salut, Government of Catalonia, Spain; Grant sponsor: NIH; Grant numbers: R01MH62873, R01MH081803; Grant sponsor: European College of Neuropsychopharmacology. �Correspondence to: Erlend J. Brevik, PsyD, and Tetyana Zayats, M.D., Ph.D., K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway. E-mail:
[email protected] (EJB);
[email protected] (TZ) Article first published online in Wiley Online Library (wileyonlinelibrary.com): 29 March 2016 DOI 10.1002/ajmg.b.32434 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. 733 http://creativecommons.org/licenses/by-nc/4.0/ http://creativecommons.org/licenses/by-nc/4.0/ 734 AMERICAN JOURNAL OF MEDICAL GENETICS PART B Aggressiveness is a behavioral trait that has the potential to be How to Cite this Article: Brevik EJ, van Donkelaar MMJ, Weber H, S�anchez-Mora C, Jacob C, Rivero O, Kittel- Schneider S, Garcia-Martı́nez I, Aebi M, van Hulzen K, Cormand B, Ramos-Quiroga JA, IMAGE Consortium, Lesch K-P, Reif A, Ribas�es M, Franke B, Posserud M-B, Johansson S, Lundervold AJ, Haavik J, Zayats T. 2016. Genome-Wide Analyses of Aggressiveness in Attention-Deficit Hyperactivity Disorder. Am J Med Genet Part B 171B:733–747. harmful to individuals and society. With an estimated herita- bility of about 40%, genetics is important in its development.We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyper- activity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggres- siveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P< 5.00e-08). the strongest signal in aadhd was observed at rs10826548,within a longnoncodingrnagene (beta¼�1.66, standard error (se)¼ 0.34, p¼ 1.07e-06), closely followed by rs35974940 in the neurotrimin gene (beta¼ 3.23, se¼ 0.67, p¼ 1.26e-06). the top gwa snps observed in aadhd showed significant enrichment of signals from both the defiant/vindic- tive dimension (fisher’s p-value¼ 2.28e-06) and the irritable dimension in cadhd (fisher’s p-value¼ 0.0061). in sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide tar- gets for further genetic exploration of aggressiveness across psychiatric disorders. � 2016 the authors. american journal of medical genetics part b: neuropsychiatric genetics published by wiley periodicals, inc. key words: adhd; aggression; gwas introduction aggressiveness can be defined as any behavior directed toward an individual with the immediate intent to cause harm [anderson and bushman, 2002]. violence, which is strongly related to aggres- siveness, is the sixth leading cause of burden of disease for people aged 15–44 years worldwide [who, 2008]. to date, most inter- ventions designed to reduce violence risk typically have small effects, reflecting our limited understanding of its causes and stressing the need for further studies [moffitt, 2005; mcguire, 2008]. as a complex phenomenon, aggressiveness spans across numer- ous facets of human behavior, ranging from emotional lability and temperamental traits (e.g., hot-tempered, short fuse, irritable) to physical violence [lesch et al., 2012]. these traits are frequently found among youth with attention deficit hyperactivity disorder (adhd), a common child and adolescent psychiatric disorder with a prevalence of about 5% and a rate of persistence into adulthood of about 50% [faraone et al., 2015]. adhd is defined by symptoms of inattention and hyperactivity/impulsivity, and youth with adhd often have co-existing disorders, some of which are closely related to aggressiveness and violence, such as conduct disorder (cd) and/or oppositional defiant disorder (odd) and disorders characterized by symptoms defined within the broader term of antisocial behavior [dalsgaard et al., 2002]. these disorders put youth with adhd at high risk of problems associated with aggressiveness in adulthood [klassen et al., 2010], especially when the aggressive behavior has an early onset [hofvander et al., 2009]. this can be illustrated by the fact that around 30% of youth and 25% of adult prison inmates are found to qualify for an adhd diagnosis [young et al., 2014]. studies of childhood aggressiveness in adults can, therefore, be of great importance to improve our understanding of adult adhd. the etiology of adhd as well as traits of aggressiveness is complex, with genetics playing an important role. the heritability of adhd has been estimated to be up to 88% across the lifespan [larsson et al., 2013], whereas the estimates of genetic influence on aggression vary across studies, collectively reaching about 40–50% [brendgen et al., 2006; tuvblad and baker, 2011]. such diversity in the estimation of aggression heritability may result from inconsis- tency in measures across studies. several different aggression measures have been utilized to assess the genetic and environmen- tal influences on its development [veroude et al., 2015], reflecting that there is no consensus regarding its definition [ramirez and andreu, 2006]. furthermore, the estimates of aggressiveness are influenced by the age of the study participants. the literature reports stability of aggressiveness between childhood and adult- hood, with adolescence as a transient period with little stability in this trait [moffitt, 2005]. genes seem to explain little variation in adolescent aggression, but are likely to account for individual differences in childhood and adult aggression [lyons et al., 1995]. also, given higher levels of aggression in males and higher genetic load inmales with antisocial behavior compared to females, it is an open question whether genetic propensity is of greater importance in one sex over the other [miles and carey, 1997; tuvblad and baker, 2011]. interestingly, similar considerations of age and sex effects are also present in studies of adhd as well as when adhd is co-morbid with aggressive behavior [faraone et al., 1991, 2015]. given that adhd and aggression often co-occur and that both traits are heritable, twin studies have noted the possibility of shared genetic etiology between adhd and aggression. a common genetic factor has been reported among adhd and symptoms of aggression in 9–10-year-old children [tuvblad et al., 2009]. likewise, it has been suggested that impulsivity and aggression are genetically mediated to a similar extent [seroczynski et al., 1999]. influenced by major theories on neuronal circuits, genetic association studies of adhd and/or aggression have been domi- nated by candidate gene studies, focusing on the regulation of brevik et al. 735 monoaminergic transmission [faraone et al., 2015; veroude et al., 2015]. in line with twin studies, these candidate gene analyses have provided further support toward a shared genetic component between adhd and aggression. many genes associated with adhd point toward the same biological mechanisms as those associated with aggressive behavior, including genes that are involved in the synthesis, binding, transport and degradation of neurotransmitters, especially dopamine and serotonin [faraone et al., 2015; veroude et al., 2015]. it has been reported, for example, that the genesmaoa, drd2, drd4, comt, slc6a4, tph1, and tph2 may contribute to the development of adhd as well as aggressive behaviors [gizer et al., 2009; vassos et al., 2014]. 5.00e-08).="" the="" strongest="" signal="" in="" aadhd="" was="" observed="" at="" rs10826548,within="" a="" longnoncodingrnagene="" (beta¼�1.66,="" standard="" error="" (se)¼="" 0.34,="" p¼="" 1.07e-06),="" closely="" followed="" by="" rs35974940="" in="" the="" neurotrimin="" gene="" (beta¼="" 3.23,="" se¼="" 0.67,="" p¼="" 1.26e-06).="" the="" top="" gwa="" snps="" observed="" in="" aadhd="" showed="" significant="" enrichment="" of="" signals="" from="" both="" the="" defiant/vindic-="" tive="" dimension="" (fisher’s="" p-value¼="" 2.28e-06)="" and="" the="" irritable="" dimension="" in="" cadhd="" (fisher’s="" p-value¼="" 0.0061).="" in="" sum,="" our="" results="" identify="" a="" number="" of="" biologically="" interesting="" markers="" possibly="" underlying="" childhood="" aggressiveness="" and="" provide="" tar-="" gets="" for="" further="" genetic="" exploration="" of="" aggressiveness="" across="" psychiatric="" disorders.="" �="" 2016="" the="" authors.="" american="" journal="" of="" medical="" genetics="" part="" b:="" neuropsychiatric="" genetics="" published="" by="" wiley="" periodicals,="" inc.="" key="" words:="" adhd;="" aggression;="" gwas="" introduction="" aggressiveness="" can="" be="" defined="" as="" any="" behavior="" directed="" toward="" an="" individual="" with="" the="" immediate="" intent="" to="" cause="" harm="" [anderson="" and="" bushman,="" 2002].="" violence,="" which="" is="" strongly="" related="" to="" aggres-="" siveness,="" is="" the="" sixth="" leading="" cause="" of="" burden="" of="" disease="" for="" people="" aged="" 15–44="" years="" worldwide="" [who,="" 2008].="" to="" date,="" most="" inter-="" ventions="" designed="" to="" reduce="" violence="" risk="" typically="" have="" small="" effects,="" reflecting="" our="" limited="" understanding="" of="" its="" causes="" and="" stressing="" the="" need="" for="" further="" studies="" [moffitt,="" 2005;="" mcguire,="" 2008].="" as="" a="" complex="" phenomenon,="" aggressiveness="" spans="" across="" numer-="" ous="" facets="" of="" human="" behavior,="" ranging="" from="" emotional="" lability="" and="" temperamental="" traits="" (e.g.,="" hot-tempered,="" short="" fuse,="" irritable)="" to="" physical="" violence="" [lesch="" et="" al.,="" 2012].="" these="" traits="" are="" frequently="" found="" among="" youth="" with="" attention="" deficit="" hyperactivity="" disorder="" (adhd),="" a="" common="" child="" and="" adolescent="" psychiatric="" disorder="" with="" a="" prevalence="" of="" about="" 5%="" and="" a="" rate="" of="" persistence="" into="" adulthood="" of="" about="" 50%="" [faraone="" et="" al.,="" 2015].="" adhd="" is="" defined="" by="" symptoms="" of="" inattention="" and="" hyperactivity/impulsivity,="" and="" youth="" with="" adhd="" often="" have="" co-existing="" disorders,="" some="" of="" which="" are="" closely="" related="" to="" aggressiveness="" and="" violence,="" such="" as="" conduct="" disorder="" (cd)="" and/or="" oppositional="" defiant="" disorder="" (odd)="" and="" disorders="" characterized="" by="" symptoms="" defined="" within="" the="" broader="" term="" of="" antisocial="" behavior="" [dalsgaard="" et="" al.,="" 2002].="" these="" disorders="" put="" youth="" with="" adhd="" at="" high="" risk="" of="" problems="" associated="" with="" aggressiveness="" in="" adulthood="" [klassen="" et="" al.,="" 2010],="" especially="" when="" the="" aggressive="" behavior="" has="" an="" early="" onset="" [hofvander="" et="" al.,="" 2009].="" this="" can="" be="" illustrated="" by="" the="" fact="" that="" around="" 30%="" of="" youth="" and="" 25%="" of="" adult="" prison="" inmates="" are="" found="" to="" qualify="" for="" an="" adhd="" diagnosis="" [young="" et="" al.,="" 2014].="" studies="" of="" childhood="" aggressiveness="" in="" adults="" can,="" therefore,="" be="" of="" great="" importance="" to="" improve="" our="" understanding="" of="" adult="" adhd.="" the="" etiology="" of="" adhd="" as="" well="" as="" traits="" of="" aggressiveness="" is="" complex,="" with="" genetics="" playing="" an="" important="" role.="" the="" heritability="" of="" adhd="" has="" been="" estimated="" to="" be="" up="" to="" 88%="" across="" the="" lifespan="" [larsson="" et="" al.,="" 2013],="" whereas="" the="" estimates="" of="" genetic="" influence="" on="" aggression="" vary="" across="" studies,="" collectively="" reaching="" about="" 40–50%="" [brendgen="" et="" al.,="" 2006;="" tuvblad="" and="" baker,="" 2011].="" such="" diversity="" in="" the="" estimation="" of="" aggression="" heritability="" may="" result="" from="" inconsis-="" tency="" in="" measures="" across="" studies.="" several="" different="" aggression="" measures="" have="" been="" utilized="" to="" assess="" the="" genetic="" and="" environmen-="" tal="" influences="" on="" its="" development="" [veroude="" et="" al.,="" 2015],="" reflecting="" that="" there="" is="" no="" consensus="" regarding="" its="" definition="" [ramirez="" and="" andreu,="" 2006].="" furthermore,="" the="" estimates="" of="" aggressiveness="" are="" influenced="" by="" the="" age="" of="" the="" study="" participants.="" the="" literature="" reports="" stability="" of="" aggressiveness="" between="" childhood="" and="" adult-="" hood,="" with="" adolescence="" as="" a="" transient="" period="" with="" little="" stability="" in="" this="" trait="" [moffitt,="" 2005].="" genes="" seem="" to="" explain="" little="" variation="" in="" adolescent="" aggression,="" but="" are="" likely="" to="" account="" for="" individual="" differences="" in="" childhood="" and="" adult="" aggression="" [lyons="" et="" al.,="" 1995].="" also,="" given="" higher="" levels="" of="" aggression="" in="" males="" and="" higher="" genetic="" load="" inmales="" with="" antisocial="" behavior="" compared="" to="" females,="" it="" is="" an="" open="" question="" whether="" genetic="" propensity="" is="" of="" greater="" importance="" in="" one="" sex="" over="" the="" other="" [miles="" and="" carey,="" 1997;="" tuvblad="" and="" baker,="" 2011].="" interestingly,="" similar="" considerations="" of="" age="" and="" sex="" effects="" are="" also="" present="" in="" studies="" of="" adhd="" as="" well="" as="" when="" adhd="" is="" co-morbid="" with="" aggressive="" behavior="" [faraone="" et="" al.,="" 1991,="" 2015].="" given="" that="" adhd="" and="" aggression="" often="" co-occur="" and="" that="" both="" traits="" are="" heritable,="" twin="" studies="" have="" noted="" the="" possibility="" of="" shared="" genetic="" etiology="" between="" adhd="" and="" aggression.="" a="" common="" genetic="" factor="" has="" been="" reported="" among="" adhd="" and="" symptoms="" of="" aggression="" in="" 9–10-year-old="" children="" [tuvblad="" et="" al.,="" 2009].="" likewise,="" it="" has="" been="" suggested="" that="" impulsivity="" and="" aggression="" are="" genetically="" mediated="" to="" a="" similar="" extent="" [seroczynski="" et="" al.,="" 1999].="" influenced="" by="" major="" theories="" on="" neuronal="" circuits,="" genetic="" association="" studies="" of="" adhd="" and/or="" aggression="" have="" been="" domi-="" nated="" by="" candidate="" gene="" studies,="" focusing="" on="" the="" regulation="" of="" brevik="" et="" al.="" 735="" monoaminergic="" transmission="" [faraone="" et="" al.,="" 2015;="" veroude="" et="" al.,="" 2015].="" in="" line="" with="" twin="" studies,="" these="" candidate="" gene="" analyses="" have="" provided="" further="" support="" toward="" a="" shared="" genetic="" component="" between="" adhd="" and="" aggression.="" many="" genes="" associated="" with="" adhd="" point="" toward="" the="" same="" biological="" mechanisms="" as="" those="" associated="" with="" aggressive="" behavior,="" including="" genes="" that="" are="" involved="" in="" the="" synthesis,="" binding,="" transport="" and="" degradation="" of="" neurotransmitters,="" especially="" dopamine="" and="" serotonin="" [faraone="" et="" al.,="" 2015;="" veroude="" et="" al.,="" 2015].="" it="" has="" been="" reported,="" for="" example,="" that="" the="" genesmaoa,="" drd2,="" drd4,="" comt,="" slc6a4,="" tph1,="" and="" tph2="" may="" contribute="" to="" the="" development="" of="" adhd="" as="" well="" as="" aggressive="" behaviors="" [gizer="" et="" al.,="" 2009;="" vassos="" et="" al.,="">