Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.
Department of Psychology, Michigan State University, East Lansing, Michigan.
Psychophysiology. 2019 May;56(5):e13325. doi: 10.1111/psyp.13325. Epub 2019 Jan 4.
The modulation of the startle response (SR) by threatening stimuli (fear-potentiated startle; FPS) is a proposed endophenotype for disorders of the fearful-fearlessness spectrum. FPS has failed to show evidence of heritability, raising concerns. However, metrics used to index FPS-and, importantly, other conditional phenotypes that are dependent on a baseline-may not be suitable for the approaches used in genetic epidemiology studies. Here, we evaluated multiple metrics of FPS in a population-based sample of preadolescent twins (N = 569 from 320 twin pairs, M = 11.4) who completed a fear-conditioning paradigm with airpuff-elicited SR on two occasions (~1 month apart). We applied univariate and multivariate biometric modeling to estimate the heritability of FPS using several proposed standardization procedures. This was extended with data simulations to evaluate biases in heritability estimates of FPS (and similar metrics) under various scenarios. Consistent with previous studies, results indicated moderate test-retest reliability (r = 0.59) and heritability of the overall SR (h = 34%) but poor reliability and virtually no unique genetic influences on FPS when considering a raw or standardized differential score that removes baseline SR. Simulations demonstrated that the use of differential scores introduces bias in heritability estimates relative to jointly analyzing baseline SR and FPS in a multivariate model. However, strong dependency of FPS on baseline levels makes unique genetic influences virtually impossible to detect regardless of methodology. These findings indicate that FPS and other conditional phenotypes may not be well suited to serve as endophenotypes unless such codependency can be disentangled.
惊吓反应（SR）受威胁刺激的调制（恐惧增强的惊吓；FPS）是恐惧-无畏谱障碍的一种拟议的内表型。FPS 未能显示出遗传的证据，引起了人们的关注。然而，用于索引 FPS 的指标 - 以及重要的是，其他依赖于基线的条件表型 - 可能不适合遗传流行病学研究中使用的方法。在这里，我们在基于人群的青春期前双胞胎样本中评估了 FPS 的多种指标（来自 320 对双胞胎的 569 名，M = 11.4），他们在两次（约相隔 1 个月）用空气喷发来引出惊吓反应的恐惧条件范式中完成了实验。我们应用单变量和多变量生物计量模型，使用几种建议的标准化程序来估计 FPS 的遗传力。通过数据模拟扩展了该方法，以评估 FPS（和类似指标）的遗传力估计值在各种情况下的偏差。与先前的研究一致，结果表明，整体 SR 的测试-重测可靠性适中（r = 0.59），遗传力为 34%（h = 34%），但当考虑去除基线 SR 的原始或标准化差分得分时，FPS 的可靠性很差，几乎没有独特的遗传影响。模拟表明，与在多变量模型中联合分析基线 SR 和 FPS 相比，使用差分得分会导致遗传力估计值产生偏差。然而，FPS 对基线水平的强烈依赖性使得无论采用何种方法，独特的遗传影响都几乎不可能被检测到。这些发现表明，FPS 和其他条件表型可能不适合作为内表型，除非可以解开这种依存关系。
