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Psychophysiology. 2019 Jan 4:e13325. doi: 10.1111/psyp.13325. [Epub ahead of print]

Fear-potentiated startle response as an endophenotype: Evaluating metrics and methods for genetic applications.

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Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.
Department of Psychology, Michigan State University, East Lansing, Michigan.
Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Department of Psychology, Virginia Commonwealth University, Richmond, Virginia.
Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.


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, Mage = 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 (h2 = 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.


endophenotype; fear-potentiated startle; genetic epidemiology; heritability; preadolescents; startle blink


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