Brain electrophysiological endophenotypes for externalizing psychopathology: a multivariate approach

Abnormalities in electrophysiological measures of stimulus-evoked brain activity (including the P3 event-related potential (ERP) and its associated delta and theta time-frequency (TF) components), and intrinsic, resting state brain activity (including EEG in the beta frequency band) have each been associated with biological vulnerability to a variety of externalizing (EXT) spectrum disorders, such as substance use disorders, conduct disorder, and antisocial behavior. While each of these individual measures has shown promise as an endophenotype for one or more aspects of EXT, we proposed that the power to identify EXT-related genes may be enhanced by using these measures collectively. Thus, we sought to explore a multivariate approach to identifying electrophysiological endophenotypes related to EXT, using measures identified in the literature as promising individual endophenotypes for EXT. Using data from our large twin sample (634 MZ and 335 DZ, male and female same-sex pairs), and fitting multivariate biometric Cholesky models, we found that these measures (1) were heritable, (2) showed significant phenotypic and genetic correlation with a general vulnerability to EXT (which is itself highly heritable), (3) showed modest phenotypic and genetic correlation with each other, and (4) were sensitive to genetic effects that differed as a function of gender. These relationships suggest that these endophenotypes are likely tapping into neurophysiological processes and genes that are both common across them and unique to each-all of which are relevant to a biological vulnerability to EXT psychopathology.