Page 205 - Biobehavioral Resilence to Stress

182 Biobehavioral Resilience to Stress

Gene Association Studies

Gene association studies seek to identify specific inherited genetic varia-

tions (known as DNA sequence “polymorphisms”) that correlate or are
overrepresented in individuals who possess certain phenotypes or “traits.”
A small number of these studies have been performed to address genetic
risk for PTSD, and only a few of their results have thus far been replicated.
Non-replication of study results is not uncommon for association studies in
general (Hirschhorn & Daly, 2005). Factors that complicate study replication
are numerous, including the fact that medical and psychiatric diseases are

complex and multifactorial, influenced in their expression and severity by a

number of genetic and nongenetic factors. Therefore, it is diffi cult to isolate

the relevance of any single factor whose influence might be obscured or con-

founded by the effects of multiple (and potentially unknown) other factors
(Lander & Schork, 1994; Lohmueller, Pearce, Pike, Lander & Hirschhorn,

2003). Scientific and methodological issues may also limit the validity or gen-
eralizability of some studies (Ioannidis, Trikalinos, Ntzani & Contopoulos-
Ioannidis, 2003; Kendler, 2005; Newton-Cheh & Hirschhorn, 2005).
Despite these limitations, researchers have pursued studies to identify

evidence of genetic influences on PTSD and related diseases and syndromes.
In fact, there is large body of work suggesting that PTSD vulnerability may be
influenced indirectly or secondarily by a specific functional polymorphism

located in the 5' region (5 HTTLPR) of the human serotonin transporter gene

(SLC6A4). This polymorphism has already been linked to depressive and
anxiety disorders (Caspi et al., 2003; Eley et al., 2004; Gillespie, Whitfi eld,
Williams, Heath & Martin, 2005; Grabe et al., 2005; Kaufman et al., 2004;
Kendler, 2005), anxiety traits (Hariri et al., 2005), and diff erential acquisi-
tion of conditioned fear and increased amygdala excitability in humans
( Garpenstrand, Annas, Ekblom, Oreland & Fredrikson, 2001; Lesch et al.,
1996). In a first published case-controlled study, Lee et al. (2005) report

evidence that the serotonin transporter gene (SLC6A4) polymorphism
moderates vulnerability to PTSD in individuals who have been exposed to
life-threatening events (Lee et al., 2005). In a less specific set of genetic stu-

dies, Koenen et al. (2003a) found that monozygotic co-twins born to PTSD
probands experienced significantly more symptoms of mood disorder than

the monozygotic co-twins of combat controls or dizygotic co-twins of veterans

diagnosed with PTSD. Th is finding suggests that genetic factors mediate a
shared familial vulnerability to the comorbidity that is frequently observed
between PTSD and major depression (Koenen et al., 2003a).

There are additional lines of evidence to suggest the possible involvement of
specific genetic factors in mediating vulnerability to the development of PTSD

and related symptoms. For example, preclinical data indicate that uncontrollable

stress is associated with serotonin and dopamine efflux in the medial prefrontal

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