Twin studies have provided valuable contributions to our understanding of PTSD. Classical twin studies have shown that genetic factors are important determinants of risk for PTSD following exposure to trauma, but the same studies also confirm the importance of environmental factors as well. The twin method also demonstrates that we cannot simply rely on “common sense” notions of what constitutes an environmental factor. Indeed, the studies of Lyons et al. (1993)
and Stein et al. (2002)
indicate that variation in exposure to a traumatic event—the one thing that may seem most clearly environmental—is, in part, accounted for by genetic factors. This outcome makes sense if one considers the fact that the events to which one is exposed are not entirely random. For example, genetic predispositions (e.g., personality traits, susceptibility to alcohol abuse) will influence the kinds of environments that a person tends to seek out. Classical twin studies have also shown that there is substantial overlap of genetic factors that predispose to other anxiety disorders, depression, and substance abuse with PTSD.
Co-twin control studies have shown that some important associated features of PTSD, such as cognitive impairments or hippocampal volume reductions, are pre-existing risk factors rather than consequences of PTSD. These same studies have suggested that aspects of psychophysiological responding, brain metabolism, brain electrophysiology, and pain are consequences of PTSD that tend to be altered only after exposure to trauma and development of the disorder. It was suggested that at least one cognitive process—recall intrusions—was also a sequela of trauma exposure rather than a vulnerability indicator. There was also a suggestion, based on small differences between MZ twins within PTSD-discordant pairs, that in addition to being risk/protective factors, some cognitive processes may undergo further acquired impairment as a result of trauma exposure. In other words, abnormalities may be both risk factors and features that continue to be exacerbated post-onset.
Overall, the findings suggest possible neurodevelopmental risk factors for PTSD (e.g., CSP, neurological soft signs, general cognitive ability) as well as factors that may affect frontal-limbic circuitry. The latter is suggested by hippocampal and anterior cingulate findings as well as event-related potential and cognitive findings implicating executive, attentional, and episodic memory functions. A greater focus on prefrontal cortex is probably warranted. Evidence is also accumulating from co-twin control studies suggesting the importance of a variety of chronic pain conditions as sequelae of PTSD. Thus, comorbid physical as well as psychiatric disorders are important, although twin studies suggest that they are often different with respect to being risk factors versus consequences.
Given the genetic overlap with other psychiatric disorders, one obvious avenue with regard to potential pharmacological treatment is, in part, the use of medications that are successful in treating those related disorders. Perhaps the next logical step would be to focus on medications aimed at treating aspects of PTSD that have been shown to be consequences of the illness. Behaviors associated with psychophysiological and electrophysiological abnormalities as well as chronic pain might be good initial targets.
On the other hand, much of the currently available data to which we just referred are at best suggestive. The vast majority of findings stem from only two samples: the VET Registry in which the focus is most often on combat-related trauma during the Vietnam war; and Canadian twin sample of Jang, Stein and colleagues. Much of this work has also been conducted on men. It is also important to note that virtually all of the co-twin control studies have come from the same research group of Pitman and colleagues. These are valuable studies, but generalizability may be limited because all of the studies are of Vietnam era men who have been tested in the same laboratory, and because the sample sizes tend to be quite small.
Small sample size is a problem for many co-twin control designs because it is often difficult to find participants meeting the study criteria. Although large sample size is a positive feature of any study, the need for very large sample sizes for classical twin studies can be a drawback of twin research on PTSD. It is difficult to find adequately large twin samples with a large enough subset of participants with PTSD, and creating a new twin sample is particularly costly and time-consuming. The inability to identify specific genes is another commonly referred to limitation of the twin method. Ultimately, it will, of course, be important to identify key polymorphisms that are associated with risk for, or protection from, PTSD. It will also be important to clarify epigenetic changes that are associated with PTSD (e.g., changes in gene expression or DNA methylation). However, the problem of the missing heritability for so many phenotypes (Maher, 2008
) clearly indicates that high-throughput methods allowing for the rapid examination of hundreds of thousands of single nucleotide polymorphisms or CpG sites has not provided a simple solution in the search for genes associated with PTSD or almost any other condition. The need to refine the definition of the phenotype and elucidate phenotypes that do or do not share genetic variance are two of the possible rate-limiting factors for gene identification. Twin methods are quite useful in this regard. Consequently, we think that twin methods provides a key complement to molecular genetic studies of PTSD and other conditions (Kremen and Lyons, 2010
Clearly more twin studies are needed that focus on non-combat trauma and on women. This is beginning to change as there are studies in their early stages that focus on women in the University of Washington Twin Registry (Afari et al., 2006
). There has not been another veteran twin registry since the VET Registry, which included male twins who served in the military at some time between 1965 and 1975 (Eisen et al., 1987
). The creation of a new twin registry focused on younger veterans of the wars in Iraq and Afghanistan is something that could substantially enhance research in this area. Such a registry would be able to address cohort differences that may be due to lifestyle differences in the different generations and to the differences in the combat experiences of the different wars. Moreover, this new registry would include women and more ethnic minorities than the VET Registry.
Finally, it should be noted that genes are anonymous in the twin method. The design is not informative as to which specific genes are involved or how many. It can, nevertheless, be very useful for identifying optimal phenotypes for genetic association studies. Moreover, recent epigenetic studies indicate that gene expression and DNA methylation (e.g., McGowan et al., 2009
; Yehuda et al., 2009
) are likely to be very important for understanding PTSD, and these would have obvious potential value for drug development. Twins, particularly MZ twins, can be extremely valuable in the study of gene expression or DNA methylation or histone acetylation. Many factors other than trauma can affect these processes and, thus, represent potential confounds. Using an MZ co-twin control design controls for many potential confounds and substantially reduces error because twins within a pair are genotypically identical and have also shared the same rearing environment. These features make this a powerful design for epigenetic studies. This is yet another way in which the twin perspective can continue to make important contributions and to complement non-genetic studies as well as genetic association studies of PTSD.