The heritability of P300 amplitude in 18-year-olds is robust to adolescent alcohol use

Abstract

P3 amplitude reduction (P3AR) is associated with adolescent alcohol use (AAU) and highly heritable, suggesting that P3AR may index a genetic predisposition (e.g., an endophenotype) for AAU. However, because P3AR and AAU covary naturally in the population, these observations are also consistent with P3AR reflecting neurotoxic effects of AAU on the developing adolescent brain. In this report, we describe the use of recent advancements in biometric modeling to examine changes in the genetic and environmental contributions to variability in P3 amplitude related to cumulative AAU by late adolescence in a large community-based twin sample. We found that the genetic and environmental contributions to variability in P3 amplitude were unaffected by AAU. This suggests that P3AR indexes risk for alcoholism independent of any deleterious effect of AAU on adolescent brain development.

Figure 1. Gene-Environment Interplay in P300 Amplitude by Source of Variance

Plausible exemplars of moderation of P300 amplitude by adolescent alcohol use (AAU). The X-axis represents the range, from low to high, of AAU. The Y-axis represents variance in P300 amplitude accounted for by each model component at that level of AAU. In Figure 1a, the two lines represent variance components: A = genetic, E = non-shared environment; drawn to scale based on the results of a meta-analysis of P300 amplitude heritability studies (van Beijsterveldt & van Baal, 2002) and from our lab (Yoon, Iacono, Malone, & McGue, 2006), where approximately 60% of the variability in P300 amplitude was estimated to be due to A and approximately 40% due to E. Although moderation may also be present in C, the shared environment, if exposure to alcohol creates similarity between twins for P300 amplitude regardless of genetic similarity. C is not included in this figure because the meta-analysis indicated that P300 amplitude variability could be explained solely by contributions from A and E and to ease presentation. Figure 1b represents an example of moderation of the genetic influences to P300 amplitude across the range of AAU. Figure 1c represents an example of moderation of the non-shared environmental influence to P300 amplitude across the range of AAU. Consistent with the definition of heritability as the relative influence of genes on average across all environments experienced by participants, the estimated influence of A and E are approximately equal (A=60%, E=40%) at the midpoint of the X-axis of each figure.

Figure 2. Grand mean waveforms at PZ in adolescents at age 18 by top and bottom deciles on AAU

Figure 3. Path diagram of a biometric moderator model with adolescent alcohol use (AAU) moderating the genetic and environmental influences on P300 amplitude at age 18 (P300)

Each of the paths impacting P300 is a linear function that combines an overall coefficient separate from the moderator variable (e.g., a₂₁) with the product of a coefficient that indexes the moderation of P300 by AAU on that path (β_Xa21) multiplied by the level of the moderator (M). The endophenotype model is simply the moderator model with the six moderation terms (β_X) set to zero. A=genetic variance, C=shared environmental variance, E=nonshared environmental variance.

Figure 4. Plot of ACE components for P300 amplitude in the Endophenotype model (left) and the Alcohol Exposure model (right)

The X-axis is marked at 5 z-score units of adolescent alcohol use to help ease presentation. The three lines represent variance components: A = genetic, C = shared environment, E = non-shared environment. The Y axis is percent of variance in P300 amplitude accounted for by that component at that level of adolescent alcohol use (AAU). The left panel contains the ACE components as calculated in the Endophenotype model across the range of AAU. The right panel plots the ACE estimate for P300 amplitude from the Alcohol Exposure model across the range of AAU.

Figure 4. Plot of ACE components for P300 amplitude in the Endophenotype model (left) and the Alcohol Exposure model (right)

The X-axis is marked at 5 z-score units of adolescent alcohol use to help ease presentation. The three lines represent variance components: A = genetic, C = shared environment, E = non-shared environment. The Y axis is percent of variance in P300 amplitude accounted for by that component at that level of adolescent alcohol use (AAU). The left panel contains the ACE components as calculated in the Endophenotype model across the range of AAU. The right panel plots the ACE estimate for P300 amplitude from the Alcohol Exposure model across the range of AAU.