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Posttraumatic Stress Disorder 187

other factors (e.g., intelligence, neurological soft signs, personality, coping

style, physiologic responsiveness) that might be due to direct genetic eff ects
or to phenotypic changes stemming from exposure to stress in early life
(Grigorenko, 2005; Kramer et al., 2005; McNally, 2003).

Given the difficulties inherent to identifying specific candidate genes
for a PTSD phenotype, an alternative strategy is to address subclinical but
measurable “endophenotypes” that can be associated with PTSD based
upon data derived from preclinical models and other biological abnormali-
ties associated with PTSD. For example, FPS provides a measure of fear-
based learning (acquisition learning) that can be modeled in animals and is
thought to occur reliably in response to life-threatening events. Research-
ers have recently made significant progress toward understanding the neu-

rocircuitry and neurochemical basis of fear-based learning (Bonne et al.,
2004; Charney, 2004).
Step 5: Test for an interaction. In order to test a putative interaction between
a gene and environment, the researcher, among other things, must include
a cohort that is sufficient to represent genetic variation in the population- at-

large and a cohort or sample of individuals who vary in their responses to the
environmental pathogen(s) of interest (Collins, Lau & De La Vega, 2004; Moffi tt
et al., 2005). In the context of PTSD research, longitudinal cohort studies are
desirable because they provide an opportunity to observe subjects before and
after trauma exposure and onset of PTSD symptoms. Unfortunately, while

such studies are theoretically possible in cohorts of individuals exposed to
high-risk environments (e.g., war or law enforcement), they can be diffi cult to
execute for a number of reasons, including cost. A longitudinal study of PTSD
would have to assume that the base rate of potentially traumatic stress would

be sufficiently severe and frequent to produce high enough rates of PTSD in
cohort subjects to allow use of standard statistical measures. Th ese conditions
cannot be met in the average civilian environment, because even though the
prevalence of PTSD is higher than for many other mental disorders, it is not
possible to predict a priori who will be exposed to trauma, and consequently be

potentially susceptible to PTSD. Thus, it would be necessary to longitudinally
follow large numbers of subjects for an unpredictable length of time. Conse-

quently, researchers typically favor more effi cient and affordable designs such
as those that add trauma exposure information to more conventional gene-

association studies (Moffitt et al., 2005; Yang & Khoury, 1997).

Step 6: Evaluate whether effects of the gene–environment interaction extend

beyond initially hypothesized relationships. The researcher should take an
additional exploratory step to determine if the gene–environment inter-
action of interest has effects that extend to other genes or environmental

pathogens, which activate the same neural or physiologic systems to produce
similar outcomes.

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