Pleiotropic genetic influences on event-related brain potentials and alcoholism

Several groups have demonstrated reduced P3(00) amplitudes of the event-related brain potential in abstinent alcoholics and their offspring, making P3 a promising quantitative marker for liability to alcoholism. To assess whether correlations between P3 amplitude and alcoholism stem from shared genetic influences, we performed bivariate genetic analyses on these traits. Visual P3s were recorded from 19 electrodes for 607 individuals in 103 families ascertained through an alcoholic proband with two first degree relatives who also met COGA alcohol dependence criteria (DSM-III-R and Feighner definite). Subjects were genotyped for approximately 275 polymorphic markers spaced at approximately 15 cM intervals. Bivariate quantitative genetic and linkage analyses were performed with SOLAR. DSM-IV, ICD-10, and COGA diagnoses were analyzed with similar results. Genetic correlations were strongest with the COGA diagnosis. P3 amplitude at all leads showed negative genetic correlations with alcoholism, indicating the presence of pleiotropic loci which reduce P3 and increase liability to disease. Environmental correlations were not significantly different from zero. Genetic correlations were strongest at central and temporal leads (-0.61 to -0.70, P < 0.01) and weakest at the occipital leads (-0.04, P > 0.10). We performed bivariate linkage screens of the three diagnoses with P3 amplitude at Cz. The pattern of results was similar across diagnoses, but the strongest evidence for linkage was obtained with DSM-IV. A chromosome 4 region near ADH (LOD = 5.79) strongly influenced liability to alcoholism (P = 1.2 × 10^-7, with evidence for pleiotropic effects on P3 (P = 8.5 × 10^-4). A region on 6q (LOD = 3.49) had a strong influence on P3 (P = 3.4 × 10^-5), with evidence for weaker pleiotropic effects on alcoholism (P = 0.028).