title: How phenotype and developmental stage affect the genes we find: GABRA2 and impulsivity.
abstract: BACKGROUND
  The detection and replication of genes involved in psychiatric outcome has been notoriously difficult. Phenotypic measurement has been offered as one explanation, although most of this discussion has focused on problems with binary diagnoses.
  
  
  OBJECTIVE
  This article focuses on two additional components of phenotypic measurement that deserve further consideration in evaluating genetic associations: (1) the measure used to reflect the outcome of interest, and (2) the developmental stage of the study population. We focus our discussion of these issues around the construct of impulsivity and externalizing disorders, and the association of these measures with a specific gene, GABRA2.
  
  
  METHODS
  Data were analyzed from the Collaborative Study on the Genetics of Alcoholism Phase IV assessment of adolescents and young adults (ages 12-26; N = 2,128).
  
  
  METHODS
  Alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder symptoms were measured by psychiatric interview; Achenbach youth/adult self-report externalizing scale; Zuckerman Sensation-Seeking scale; Barratt Impulsivity scale; NEO extraversion and consciousness.
  
  
  RESULTS
  GABRA2 was associated with subclinical levels of externalizing behavior as measured by the Achenbach in both the adolescent and young adult samples. Contrary to previous associations in adult samples, it was not associated with clinical-level DSM symptom counts of any externalizing disorders in these younger samples. There was also association with sensation-seeking and extraversion, but only in the adolescent sample. There was no association with the Barratt impulsivity scale or conscientiousness.
  
  
  CONCLUSIONS
  Our results suggest that the pathway by which GABRA2 initially confers risk for eventual alcohol problems begins with a predisposition to sensation-seeking early in adolescence. The findings support the heterogeneous nature of impulsivity and demonstrate that both the measure used to assess a construct of interest and the age of the participants can have profound implications for the detection of genetic associations.
authors.affiliation: Department of Psychiatry, Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA. ddick@vcu.edu
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Dick
authors.forename: Fazil
authors.initials: F
authors.lastname: Aliev
authors.forename: Shawn
authors.initials: S
authors.lastname: Latendresse
authors.forename: Bernice
authors.initials: B
authors.lastname: Porjesz
authors.forename: Marc
authors.initials: M
authors.lastname: Schuckit
authors.forename: Madhavi
authors.initials: M
authors.lastname: Rangaswamy
authors.forename: Victor
authors.initials: V
authors.lastname: Hesselbrock
authors.forename: Howard
authors.initials: H
authors.lastname: Edenberg
authors.forename: John
authors.initials: J
authors.lastname: Nurnberger
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.forename: Laura
authors.initials: L
authors.lastname: Bierut
authors.forename: Jen
authors.initials: J
authors.lastname: Wang
authors.forename: Kathy
authors.initials: K
authors.lastname: Bucholz
authors.forename: Samuel
authors.initials: S
authors.lastname: Kuperman
authors.forename: John
authors.initials: J
authors.lastname: Kramer
mesh_terms: D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology; D000987:Antisocial Personality Disorder / Q000235:genetics / Q000523:psychology; D002648:Child; D019955:Conduct Disorder / Q000235:genetics / Q000523:psychology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007175:Impulsive Behavior / Q000235:genetics* / Q000523:psychology; D007406:Interview, Psychological; D008297:Male; D010641:Phenotype; D011569:Psychiatric Status Rating Scales; D011963:Receptors, GABA-A / Q000235:genetics*; D018570:Risk Assessment; D019966:Substance-Related Disorders / Q000235:genetics / Q000523:psychology
chemical_list: C484841:GABRA2 protein, human; D011963:Receptors, GABA-A
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