increases in negative affect while trying to quit smoking (35). To claim that these diverse outcomes are heterotypic manifestations of a unifying genetic vulnerability to stress reflected in the 5-HTTLPR S allele requires a theory that specifies the unifying mechanism. The leading theory (1, 36) is that the 5-HTTLPR is a genetic substrate for a latent personality trait, termed negative affectivity or neuroticism. Negative affectivity prospectively predicts risk for all stress-related psychiatric disorders (37). In theory, 5-HTTLPR S-carriers are characterized by the stable trait of negative affectivity that is converted to psychopathology only under conditions of stress, just as glass is always characterized by the trait of brittleness but shatters only when a stone is thrown. Negative affectivity represents the potential for excitability of anxiety and fear neural circuits, and is characterized by an attentional bias toward negatively valenced information and a cognitive sensitivity to perceive threat (38). This trait is operationalized in all experimental tests of the 5-HTTLPR G×E hypothesis, reviewed next.
