Genes mediate the association between P3 amplitude and externalizing disorders.

Over the past 20 years, a substantial body of research has established a link between alcoholism and reduced amplitude of the P3 (third positive) component of the brain event-related potential (Polich, Pollock, & Bloom, 1994; Porjesz, Begleiter, Bihari, & Kissin, 1987). Reduced P3 amplitude is associated not only with active symptoms of alcoholism, but also with risk for alcoholism. Specifically, prior to the onset of drinking, reduced P3 has been demonstrated in sons of alcoholics in comparison to controls without a family history of alcoholism (Begleiter, Porjesz, Bihari, & Kissin, 1984). Additionally, reduced P3 amplitude prospectively predicts the emergence of later alcohol problems in persons asymptomatic at the time of the baseline assessment (Iacono, Carlson, Malone, & McGue, 2002). These lines of evidence support the hypothesis that reduced P3 amplitude is a biological risk marker or endophenotype for alcoholism, that is, a laboratory measure of nervous system activity whose genetic underpinnings overlap with the genetic risk factors associated with alcoholism (Begleiter & Porjesz, 1999; Iacono, 1998). Other research, however, has demonstrated that reduced P3 amplitude is associated not only with alcoholism but with other psychiatric disorders characterized by behavioral disinhibition, including illicit drug dependence (Bauer, 2001; Biggins, MacKay, Clark, & Fein, 1997; Brigham, Moss, Murrelle, Kirisci, & Spinelli, 1997), nicotine dependence (Anokhin et al., 2000), and child and adult antisocial behavior (Bauer & Hesselbrock, 1999, 2001, 2003; Costa et al., 2000; Hesselbrock, Bauer, O’Connor, & Gillen, 1993). In a rather comprehensive analysis, Iacono et al. (2002) reported the associations between P3 amplitude and several psychiatric disorders in a large community sample of adolescent male twins, and found reduced P3 amplitude was associated with a spectrum of substance use and disinhibited behavior disorders, including alcohol dependence, illicit drug dependence, nicotine dependence, attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and antisocial personality disorder (ASPD). Additionally, persons with comorbid conditions evinced the greatest reduction in P3 amplitude, and lower P3 amplitude at age 17 predicted the development of these disorders at age 20. Furthermore, fathers’ diagnostic status on disinhibitory disorders was also associated with reduced P3 amplitude in their adolescent sons, indicating a familial association between P3 and externalizing tendencies. These results provide strong evidence that reduced P3 amplitude is a marker for disinhibitory syndromes in general rather than for alcoholism specifically. These results are also consistent with epidemiological investigations that have identified a broad risk factor, typically referred to as Externalizing, that accounts for comorbid relations among disinhibitory disorders (Krueger, 1999; Krueger, Caspi, Moffitt, & Sliva, 1998). Large-sample twin studies have since shown that this general vulnerability to externalizing disorders is primarily attributable to genetic influences, and that this general vulnerability accounts for the majority of the genetic risk factors associated with each disorder in the spectrum (Kendler, Prescott, Myers, & Neale, 2003; Krueger et al., 2002; Young, Stallings, Corley, Krauter, & Hewitt, 2000). In addition, heritability estimates for the general vulnerability factor (h2 = .81–.85) are notably greater than heritability estimates for individual disorders (h2 = .35–.60; Fu et al., 2002; Heath et al., 1997; Jacobson, Prescott, & Kendler, 2002; Kendler, Jacobson, Prescott, & Neale, 2003; Lyons et al., 1995; Slutske et al., 1998; Tsuang et al., 1998; van den Bree, Svikis, & Pickens, 1998). These findings, which indicate that this general vulnerability accounts for much of the genetic risk associated with individual externalizing disorders, suggest that this Externalizing factor might also account for associations between specific disinhibitory disorders and biological markers such as P3 amplitude. Patrick et al. (2006) directly tested the hypothesis that reduced P3 amplitude is a marker for the general vulnerability to externalizing disorders. Using a measure of the Externalizing factor consisting of scores on the first principal component extracted from symptoms of alcohol and drug dependence, conduct disorder, and adult antisocial behavior (the adult criteria for ASPD), these investigators found that: (1) reduced P3 amplitude was significantly related to scores on this factor indexing the general vulnerability to externalizing disorders, and (2) scores on this broad factor accounted for associations between the individual disorders and P3 amplitude (i.e., no residual association with any individual disorder was significant after variance in the general factor was included in a prediction model). These results further demonstrate that the association between reduced P3 amplitude and alcoholism is nonspecific, that is, it arises from the fact that alcoholism is one indicator of a general vulnerability to externalizing disorders. The present investigation extends the findings of Patrick et al. (2006) by delineating the genetic and environmental contributions to the association between P3 amplitude and the general vulnerability to externalizing disorders. Although the research on P3 amplitude as a biological marker of externalizing disorders rests on the assumption of a common genetic diathesis (Begleiter & Porjesz, 1999; Iacono, 1998), the hypothesis that the relation between the two is mediated by genes has yet to be directly tested. The primary reason is that such an analysis requires a genetically informative sampling design entailing large samples of individuals with varying degrees of genetic relatedness (e.g., monozygotic [MZ] and dizygotic [DZ] twins; Neale & Cardon, 1992). The current investigation was intended to fill this gap in the literature. The sample for the current study consisted of 1196 male twins—a sample size large enough to provide reliable and accurate parameter estimates of the heritability of P3 amplitude as well as the magnitude of its overlap with the genetic risk for externalizing disorders (Neale & Cardon, 1992). In addition, the sample included two, nonoverlapping age cohorts of approximately equal size, both drawn from the community—providing for an internal replication of findings that enhances the likelihood that the results will generalize to the population. On the basis of previous findings, we predicted that P3 amplitude and the general vulnerability to externalizing disorders would each be highly heritable (Katsanis, Iacono, McGue, & Carlson, 1997; Kendler, Prescott, et al., 2003; Krueger et al., 2002;Young et al., 2000). Our second, crucial prediction was that most if not all of the association between P3 amplitude and the general vulnerability to externalizing disorders would be attributable to genetic factors. Finally, consistent with studies that have examined associations between single-gene markers and psychiatric disorders (e.g., Faraone, Doyle, Mick, & Biederman, 2001; Faraone et al., 2005), we predicted that P3 amplitude would account for a modest, but reliable (i.e., replicable) portion of the overall genetic variance for the general vulnerability to externalizing disorders.