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Evidence for Genes on Chromosome 2 Contributing to Alcohol Dependence with Conduct Disorder and Suicide Attempts Danielle M

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Evidence for Genes on Chromosome 2 Contributing to Alcohol Dependence with Conduct Disorder and Suicide Attempts Danielle M RESEARCH ARTICLE Neuropsychiatric Genetics Evidence for Genes on Chromosome 2 Contributing to Alcohol Dependence With Conduct Disorder and Suicide Attempts Danielle M. Dick,1* Jacquelyn Meyers,1 Fazil Aliev,1 John Nurnberger Jr.,2 John Kramer,3 Sam Kuperman,3 Bernice Porjesz,4 Jay Tischfield,5 Howard J. Edenberg,2 Tatiana Foroud,2 Marc Schuckit,6 Alison Goate,7 Victor Hesselbrock,8 and Laura Bierut7 1Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 2Indiana University School of Medicine, Indianapolis, Indiana 3University of Iowa College of Medicine, Iowa City, Iowa 4SUNY Health Science Center at Brooklyn, Brooklyn, New York 5Rutgers University, Piscataway, New Jersey 6University of California, San Diego VA Medical Center, San Diego, California 7Washington University in St. Louis, St. Louis, Missouri 8University of Connecticut Health Center, Farmington, Connecticut Received 27 August 2009; Accepted 22 February 2010 Twin studies provide strong evidence that there is a shared genetic liability that predisposes to a number of different How to Cite this Article: psychiatric outcomes related to behavioral disinhibition. Dick DM, Meyers J, Aliev F, Nurnberger J Jr, Further, alcohol dependence comorbid with other disinhibitory Kramer J, Kuperman S, Porjesz B, Tischfield J, disorders is particularly heritable. Chromosome 2p14-2q14.3 Edenberg HJ, Foroud T, Schuckit M, Goate A, has been linked to multiple psychiatric conditions related to Hesselbrock V, Bierut L. 2010. Evidence for behavioral undercontrol. In the Collaborative Study on the Genes on Chromosome 2 Contributing to Genetics of Alcoholism (COGA), we previously reported Alcohol Dependence With Conduct Disorder linkage to this region with alcohol dependence (AD), suicide and Suicide Attempts. attempts (SUI), and conduct disorder (CD). In this study, – we follow-up on these previous reports of linkage by com- Am J Med Genet Part B 153B:1179 1188. bining the phenotypes in analyses that jointly consider the presence of multiple conditions. Linkage analyses of the com- bined phenotype of AD with CD or SUI results in a maximum Key words: alcoholism; genetics; linkage; association; behav- LOD score of 5.4 in this region. In addition to this primary ioral disinhibition linkage peak, independent samples have reported linkage to other alcohol-related phenotypes across chromosome 2. Accordingly, we followed-up these linkage signals by testing Additional Supporting Information may be found in the online version of for association with SNPs across chromosome 2 in a case– this article. control sample, in which a subset of the cases consisted of Grant sponsor: NARSAD; Grant numbers: U10AA008401, N01-HG- alcohol-dependent probands from the linkage sample. We 65403; Grant sponsor: National Institute on Alcohol Abuse and find evidence of association with the combined AD with CD Alcoholism (NIAAA); Grant sponsor: National Institute on Drug Abuse or SUI phenotype, with 23 genes surviving permutation (NIDA). testing. The number of associated genes across the chromosome *Correspondence to: may explain the persistent linkage findings reported on Dr. Danielle M. Dick, Ph.D., Department of Psychiatry, Virginia Institute chromosome 2 across a number of independent studies of for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298-0126. alcohol and disinhibitory phenotypes. Further, none of the E-mail: [email protected] genes were located directly under the primary COGA Published online 16 April 2010 in Wiley Online Library linkage peak, which has implications for association tests (wileyonlinelibrary.com). following-up linkage peaks. Ó 2010 Wiley-Liss, Inc. DOI 10.1002/ajmg.b.31089 Ó 2010 Wiley-Liss, Inc. 1179 1180 AMERICAN JOURNAL OF MEDICAL GENETICS PART B INTRODUCTION smoking [Straub et al., 1999; Goode et al., 2003] have also been reported on chromosome 2 in independent samples. Although Twin studies provide strong evidence of shared genetic liability linkage to a comorbid habitual smoking and alcohol dependence across a number of different psychiatric conditions. For example, phenotype has been reported to chromosome 2p in COGA [Bierut in a large study of the genetic architecture of the major common et al., 2004], the finding is largely due to the alcohol dependence psychiatric and substance use disorders, Kendler et al. [2003], phenotype. using data from the Virginia Twin Registry, demonstrated that The phenotypes of alcohol dependence, conduct disorder, and there were two broad genetic factors: one that contributed suicide attempts, which show linkage on chromosome 2, are all to externalizing disorders (alcohol dependence, drug abuse/ characterized by elements of impulsivity and behavioral under- dependence, childhood conduct disorder, and adult antisocial control. Conduct disorder is a robust predictor of both concurrent behavior) and a second that contributed to internalizing dis- and future alcohol problems [Crowley et al., 1998; Moss and Lynch, orders (major depression, generalized anxiety disorder and 2001; White et al., 2001]. Furthermore, numerous twin studies phobia). These findings have implications for gene identification indicate that the overlap between childhood conduct disorder and efforts, as they suggest that some genes may not be specific to any adult alcohol dependence is largely due to shared genetic factors one disorder, but rather, may predispose to a variety of psychiat- [Slutske et al., 1998; Krueger, 1999; Young et al., 2000; Kendler et al., ric outcomes. Furthermore, individuals meeting a psychiatric 2003]. This common genetic liability is thought to be a predisposi- diagnosis are often a heterogeneous group clinically. For exam- tion toward behavioral undercontrol/disinhibition, which can ple, in the case of alcohol dependence, affected individuals often manifest as conduct disorder in childhood and alcohol dependence vary on a number of important dimensions, including age of later in life [Slutske et al., 2002]. It has been demonstrated that onset, course of illness, and the presence of comorbid conditions GABRA2, a gene associated with alcohol dependence in adults [Cloninger, 1987; Babor et al., 1992; Hesselbrock and Hessel- [Edenberg et al., 2004; Lappalainen et al., 2005; Enoch, 2008; Soyka brock, 1994; Finn et al., 1997]. Evidence from twin and family et al., 2008] is associated with CD symptoms and externalizing studies suggests that alcohol dependence with comorbid disin- behavior in adolescents[Dick et al., 2006, 2009], providing evidence hibitory disorders may represent a more heritable form of the that variations in one gene can manifest as different conditions at disorder [Pickens et al., 1991, 1995; Johnson et al., 1996; Ohan- different stages of the life cycle. Electrophysiological endopheno- nessian et al., 2004] suggesting that comorbid, or combined, types, which are thought to index genetic vulnerability to psychiat- phenotypes may be particularly relevant for gene identification ric phenotypes, are also shared across substance use disorders and efforts. conduct disorder [Iacono et al., 1999; Porjesz et al., 2005]. For Data from the Collaborative Study on the Genetics of Alcoholism example, a reduced P3 event-related potential amplitude has been (COGA) suggest that chromosome 2p14-2q14.3 may contain a gene found among adolescents with both substance use disorders and (or genes) with pleiotropic effects on alcohol dependence and externalizing disorders [Iacono et al., 2002]. Suicide attempts related psychiatric conditions. Initially, linkage was detected near are also considerably elevated in individuals with alcohol depen- the marker D2S379 (LOD ¼ 3.0) with an alcohol dependence (AD) dence and conduct disorder [Kessler et al., 1999]. A recent study by phenotype, defined as meeting diagnostic criteria according to the Conner et al. [2009], found that proactive aggression (unemotional DSM-IIIR and Feighner classification systems [Foroud et al., 2000]. aggression executed for reward) is associated with both suicide Subsequently, linkages to the same region were identified with the attempts and suicidal ideation among inpatient substance abuse phenotypes of suicide attempts (SUI) [Hesselbrock et al., 2004] and patients. Furthermore, in the COGA adult sample, unplanned conduct disorder (CD) [Dick et al., 2003]. These findings are suicide attempts among persons with alcohol dependence are robust, with replication reported in multiple independent samples: associated with externalizing behaviors, including antisocial behav- Suicide attempts were linked to this same region of chromosome 2 ior and alcohol-related aggression [Conner et al., 2007]. Suicidal in pedigrees affected with early-onset major depression [Zubenko behavior is influenced by genetic factors [Bondy et al., 2006], and it et al., 2004] and with bipolar disorder [Willour et al., 2007]. Linkage is thought that the predisposition to suicidal behavior reflects a of conduct disorder to this region was replicated in the Irish heritable liability to personality traits such as impulsivity and Affected Sib Pair Study for Alcohol Dependence [Kendler et al., aggression [Baud, 2005]. To the extent that these characteristics 2006a]. Further analysis of a subset of the COGA pedigrees on also predispose to substance use and externalizing problems, it is whom genome-wide SNP linkage data were produced for the reasonable to hypothesize that suicidal behavior may represent Genetic Analysis Workshop 14 (GAW14)
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