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Step 7: Replicate and meta-analyze. Finally, it is important to replicate positive
results to rule out false positive or spurious findings. Unfortunately, as noted,

genetic association studies are inherently difficult to replicate (Hirschhorn,

Lohmueller, Byrne & Hirschhorn, 2002). However, resources such as the

“The Genetic Association Study Database” (http://geneticassociationdb.nih.
gov/) provide information that may help researchers to identify and under-

stand the results of other genetic association studies whose findings that can
be reconciled with new or unique observations.

Model Systems and the Genetic Basis of PTSD

The Startle Response

Model systems are routinely used to identify candidate biological pathways,
neuroanatomical circuits, and genes that may infl uence specifi c phenotypes
in human beings. For example, the startle response is a highly conserved,
cross-species phenomenon that is well-suited to translational studies of

pathology across animal and human subjects. The startle response mani-

fests as a series of involuntary reflexes elicited by a sudden, intense audi-
tory stimulus or sudden tactile stimulus to the throat or face. Th e startle
response is modulated by cortical and limbic brain regions, many of which
are abnormally activated or exhibit altered volumes in individuals who suf-
fer from anxiety disorders (Davis, 1998; Funayama, Grillon, Davis & Phelps,
2001; Gilbertson et al., 2002; Hull, 2002; Kumari et al., 2003; Lorberbaum
et al., 2004; Neumeister et al., 2004; Schneider et al., 1999; Swerdlow, Geyer

& Braff, 2001; Weike et al., 2005). The magnitude of the startle response can

be increased by the presentation of fear-inducing stimuli or by administra-
tion of anxiogenic compounds (Brown, Kalish & Farber, 1951; Davis, Walker
& Lee, 1997; Swerdlow, Geyer, Vale & Koob, 1986), and can be decreased by
the use of threat-reducing stimuli (Lang, Bradley & Cuthbert, 1990), anxio-
lytic and sedative drugs (Abduljawad, Langley, Bradshaw & Szabadi, 2001),
or sensory input in the case of prepulse inhibition (PPI) (Braff , Geyer &
Swerdlow, 2001; Geyer, Krebs-Th omson, Braff & Swerdlow, 2001; Graham,

1975; Swerdlow et al., 2001). Abnormal startle responses have been observed
in subjects with anxiety disorders (Butler et al., 1990; Ludewig et al., 2005;
Ludewig S., Ludewig K., Geyer, Hell & Vollenweider, 2002; Morgan, Gril-
lon, Southwick, Davis & Charney, 1995, 1996; Orr, Lasko, Shalev & Pitman,
1995). Children of patients with anxiety and depressive disorders also exhibit
exaggerated startle, indicating that startle responsiveness could be a marker
of vulnerability to the development of clinical anxiety (Grillon, Dierker &
Merikangas, 1998) or depression (Grillon et al., 2005). Th us, startle behavior
may be useful as a model basis for the study of both state- and trait-related
anxiety.

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