Given these multi-level factors possibly modulating the influence of COMT gene variation on anxiety and affective disorders or related phenotypes, in the present study applying an integrative approach using the same study design as in Domschke et al. [67] we set out to elucidate the main as well as interactional effects of COMT gene variation, caffeine and childhood maltreatment on the affect-modulated startle response as a neurobiological measure of emotional and motivational processes potentially related to fear- and anxiety/distress-related states. The gene discussed is COMT; the disease is Anxiety.