Abstract
Background.To better characterize brain-based mechanisms of polygenic liability for psychopathology and psychological traits, we extended our previous report (Liu et al. Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci. Psychological Medicine, 2017), focused solely on schizophrenia, to test the association between multivariate psychophysiological candidate endophenotypes (including novel measures of θ/δ oscillatory activity) and a range of polygenic scores (PGSs), namely alcohol/cannabis/nicotine use, an updated schizophrenia PGS (containing 52 more genome-wide significant loci than the PGS used in our previous report) and educational attainment.Method.A large community-based twin/family sample (N = 4893) was genome-wide genotyped and imputed. PGSs were constructed for alcohol use, regular smoking initiation, lifetime cannabis use, schizophrenia, and educational attainment. Eleven endophenotypes were assessed: visual oddball task event-related electroencephalogram (EEG) measures (target-related parietal P3 amplitude, frontal θ, and parietal δ energy/inter-trial phase clustering), band-limited resting-state EEG power, antisaccade error rate. Principal component analysis exploited covariation among endophenotypes to extract a smaller number of meaningful dimensions/components for statistical analysis.Results.Endophenotypes were heritable. PGSs showed expected intercorrelations (e.g. schizophrenia PGS correlated positively with alcohol/nicotine/cannabis PGSs). Schizophrenia PGS was negatively associated with an event-related P3/δ component [β = −0.032, nonparametric bootstrap 95% confidence interval (CI) −0.059 to −0.003]. A prefrontal control component (event-related θ/antisaccade errors) was negatively associated with alcohol (β = −0.034, 95% CI −0.063 to −0.006) and regular smoking PGSs (β = −0.032, 95% CI −0.061 to −0.005) and positively associated with educational attainment PGS (β = 0.031, 95% CI 0.003–0.058).Conclusions.Evidence suggests that multivariate endophenotypes of decision-making (P3/δ) and cognitive/attentional control (θ/antisaccade error) relate to alcohol/nicotine, schizophrenia, and educational attainment PGSs and represent promising targets for future research.
Highlights
The field of endophenotype research has identified several laboratory-based biobehavioral measures that index the genetic variance related to psychopathology and psychological traits (Anokhin, 2014; Gottesman & Gould, 2003; Gottesman & Shields, 1972; Kendler & Neale, 2010)
We previously evaluated the genetic basis of a collection of promising candidate psychophysiological endophenotypes, including resting-state EEG power; P3 and θ/δ activity; and antisaccade performance, in a community-based sample of over 4800 individuals and failed to find robust and, convincing evidence for, single genes or variants influencing any of the endophenotypes (Iacono, Malone, Vaidyanathan, & Vrieze, 2014; Malone et al 2014a, 2014b; Malone, McGue, & Iacono, 2017; Vaidyanathan et al 2014; Vrieze et al 2014b)
The three substance use polygenic scores (PGSs) were positively correlated, and all were positively correlated with the schizophrenia PGS
Summary
The field of endophenotype research has identified several laboratory-based biobehavioral measures that index the genetic variance related to psychopathology and psychological traits (Anokhin, 2014; Gottesman & Gould, 2003; Gottesman & Shields, 1972; Kendler & Neale, 2010). As detailed in a recent review of psychophysiological endophenotypes (Iacono, Malone, & Vrieze, 2017), candidate endophenotypes for a variety of psychiatric/psychological phenotypes, such as alcohol/substance use and schizophrenia, include measures of spontaneous (resting state) electroencephalogram (EEG) power, P3 event-related potential (ERP) amplitude and θ and δ oscillatory activity during a target/oddball task, and antisaccade eye-tracking error rate. We sought to extend our previous work (Liu et al 2017) by performing a comprehensive test on the association between multivariate endophenotypes and a range of PGSs, including alcohol/nicotine/cannabis use [the most commonly used substances in the United States; (Substance Abuse and Mental Health Services Administration, 2020)], educational attainment, and an updated PGS for schizophrenia in a large community-based sample of over 4800 individuals from the Minnesota Twin Family Study (MTFS). Significant findings would provide important information regarding potential biobehavioral mechanisms related to the polygenic architecture of these psychiatric/psychological phenotypes
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