Harper Jeremy, Liu Mengzhen, Malone Stephen M, McGue Matt, Iacono William G, Vrieze Scott I
Department of Psychiatry & Behavioral Sciences, University of Minnesota, Twin Cities, MN, USA.
Department of Psychology, University of Minnesota, Twin Cities, MN, USA.
Psychol Med. 2021 Mar 18;52(16):1-11. doi: 10.1017/S0033291721000763.
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.
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.
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).
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.
为了更好地描述精神病理学和心理特征的多基因易感性的脑机制，我们扩展了之前的报告（Liu等人，《用于表征已知精神分裂症基因座机制的心理生理内表型》，《心理医学》，2017年），之前的报告仅关注精神分裂症，现在我们测试多变量心理生理候选内表型（包括θ/δ振荡活动的新测量方法）与一系列多基因分数（PGS）之间的关联，这些多基因分数即酒精/大麻/尼古丁使用情况、更新后的精神分裂症PGS（比我们之前报告中使用的PGS多包含52个全基因组显著位点）以及受教育程度。
对一个基于社区的大型双胞胎/家庭样本（N = 4893）进行全基因组基因分型和推算。构建了酒精使用、规律吸烟起始、终生大麻使用、精神分裂症和受教育程度的PGS。评估了11种内表型：视觉Oddball任务事件相关脑电图（EEG）测量指标（目标相关顶叶P3波幅、额叶θ波以及顶叶δ波能量/试次间相位聚类）、带限静息态EEG功率、反扫视错误率。主成分分析利用内表型之间的协变关系提取数量较少的有意义维度/成分用于统计分析。
内表型具有遗传性。PGS显示出预期的相互关联（例如，精神分裂症PGS与酒精/尼古丁/大麻PGS呈正相关）。精神分裂症PGS与一个事件相关的P3/δ成分呈负相关[β = -0.032，非参数自助法95%置信区间（CI）为-0.059至-0.003]。一个前额叶控制成分（事件相关θ波/反扫视错误）与酒精（β = -0.034，95% CI为-0.063至-0.006）和规律吸烟PGS呈负相关（β = -0.032，95% CI为-0.061至-0.005），与受教育程度PGS呈正相关（β = 0.031，95% CI为0.003 - 0.058）。
有证据表明，决策（P3/δ）和认知/注意力控制（θ/反扫视错误）的多变量内表型与酒精/尼古丁、精神分裂症和受教育程度的PGS相关，是未来研究有前景的目标。
