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Context: 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. Design, Setting, and Participants: 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). Main Outcome Measures: 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.
Understanding the genetics of nicotine dependence can lead to targeted treatments and ultimately significantly decrease tobacco-associated morbidity and mortality. In the study of nicotine dependence, it is important to understand the behavioral progression to nicotine dependence when choosing a control group. Some researchers argue that smoking is a means of self-medicating and nicotine dependence is therefore caused by mental illness. Genome-wide association studies (GWAS) have found associations between nicotine dependence and the a5 nicotinic receptor subunit gene. This chapter postulates that there are at least two distinct biological mechanisms that alter the risk of nicotine dependence. The first biological mechanism is caused by an amino acid change in CHRNA5, in the non-synonymous SNP rs16969968. The second mechanism altering risk of nicotine dependence is through altered expression of the α5 mRNA. Associations in this region have also been found in lung disease.
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