Anxious Genes?

 

 

 

 

 

 

Anxious Genes?

Murray B. Stein MD, MPHa,b

 

 

 

Submitted to Strides

May 2010

 

 

 

 

 

 

 

 

 

a Department of Psychiatry, University of California San Diego, La Jolla, CA USA

 

b Department of Family and Preventive Medicine, University of California San Diego

 

 

 

 

           Many health problems, including psychiatric illnesses, have a genetic basis. How do we know this to be true? We often find that illnesses run in families. For example, if your parent(s) had hypertension (high blood pressure), it is more likely that you will have hypertension than someone whose parents did not. In the case of many medical problems, these can occur in family members for one of two reasons: Either they occur because families are exposed to factors in the environment that increase risk for the medical problem, or they occur because families share genes that increase risk for the medical problem. Rarely is either explanation sufficient to explain how these problems are transmitted within families; nearly all the time, it is a combination of environmental factors (e.g., diet, exercise [usually lack thereof], stress) and genetic factors that work together to result in human disease. Certainly there are exceptions to this rule where some problems are completely (or nearly completely) due to genes: a common example is Down Syndrome, a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome. But for most common health problems, environment and genes both have a role to play. Anxiety disorders are no exception to this rule.

           It is well known that anxiety disorders run in families (Low, Cui, & Merikangas, 2008; Micco et al., 2009). If a parent has panic disorder, for example, any one of his or her children is several times more likely to develop panic disorder than the child of parents without panic disorder. How do we know that there is a genetic basis for this increased likelihood of developing panic disorder? Could it not be equally likely that there is something in the environment (e.g., excess stress; high caffeine use) that increases risk for panic disorder in certain families? For the most part, we know the answer to this question as a result of twin studies. Twins can either be "identical" (monozygotic, meaning that they have the same genetic makeup) or "fraternal" (dizygotic, meaning that they are not genetically identical but rather have the same genetic similarity as siblings). If an illness had a genetic basis, we would expect it to show up more consistently in both members of identical twin pairs (who share all their genes) compared to fraternal twin pairs (who share, on average, 50% of their genes). This type of twin research has shown that all of the anxiety disorders have a moderately strong genetic basis (Hettema, Neale, & Kendler, 2001; Pauls, 2008). What this means is that there are genes - probably very many genes - that work together in ways that are as yet poorly understood - to increase the risk for anxiety disorders. The contribution of these genes, in aggregate, is moderately strong, in that genes explain at most 30-40% of the likelihood of any given individual experiencing an anxiety disorder. What this means is that the other 60-70% is not due to genes but, rather, due to environmental factors which are as yet undetermined, but almost certainly include experiences such as early childhood maltreatment, early parental loss, and chronic life stressors. In the case of one particular type of anxiety disorder, posttraumatic stress disorder (PTSD), it is obvious that life-threatening traumatic stress is needed to develop the problem; this is, in fact, part of the definition. But even in the case of PTSD, we are learning that genes have a role to play, and that genes may (partly) explain why some people develop PTSD when exposed to horrific life events (e.g., proximity to the World Trade Center at the time of the September 11, 2001 terrorist attacks) and others do not, although social factors also play a large role (Bonanno, Galea, Bucciarelli, & Vlahov, 2007).  Interestingly, PTSD has provided the opportunity to carefully examine the relationship between life stressors and genetic susceptibility, and many recent studies are coming to the conclusion that it is the interaction of particular environmental factors (e.g., poverty; lack of social support) with particular genes that yields the increased risk for PTSD(Kilpatrick et al., 2007; Norrholm & Ressler, 2009).

           We are just now beginning to identify specifically which genes increase risk for anxiety disorders (Smoller, Gardner-Schuster, & Covino, 2008). In 2010, there are no genes that have yet been shown to increase risk sufficiently that any kind of genetic testing would be warranted. Yet there is much research going on that is beginning to point to some genes that may play a role in the onset of anxiety disorders and may, in years to come, lead to the discovery and development of new treatments for anxiety disorders. For example, a gene that has been extremely well studied in the mental health field, the serotonin transporter gene, has recently been shown to have an association with panic disorder (Strug et al., 2010), meaning that a particular variant of that gene is (slightly) more common in people with panic disorder than in those without. Interestingly, this gene codes for a protein in the body that is affected by selective serotonin reuptake inhibitor (SSRI) medications that are frequently used to treat panic and other anxiety disorders (Ravindran & Stein, 2009). This same gene has been shown to be associated with some cases of obsessive compulsive disorder (OCD) (Wendland et al., 2008), but it should be noted that it is a different variant in a different part of the gene than what was seen in the panic disorder study (Strug et al., 2010).

           This seems to be a recurrent finding in the field of anxiety genetics: it has been rare to see the same variant in the same gene show up repeatedly across studies. For that reason alone, it is currently impossible to use genetic testing in any practical way to determine risk for anxiety disorders in an individual. But in other areas of mental health, very large studies are taking place that allow researchers to look not only at a few genes at a time, but to look at genes across the entire genome using very powerful methods (known as genomewide association studies, or GWAS) (Craddock et al., 2009; McCarthy et al., 2008). These studies, which are already taking place in bipolar disorder, major depression and schizophrenia and will hopefully soon take place in the anxiety disorders, promise to usher in a new era of understanding about the role of genes in anxiety disorders.

 

References

 

Bonanno, G. A., Galea, S., Bucciarelli, A., & Vlahov, D. (2007). What predicts psychological resilience after disaster? The role of demographics, resources, and life stress. J.Consult Clin.Psychol., 75, 671-682.

Craddock, N., Kendler, K., Neale, M., Nurnberger, J., Purcell, S., Rietschel, M. et al. (2009). Dissecting the phenotype in genome-wide association studies of psychiatric illness. Br.J.Psychiatry, 195, 97-99.

Hettema, J. M., Neale, M. C., & Kendler, K. S. (2001). A review and meta-analysis of the genetic epidemiology of anxiety disorders. American Journal of Psychiatry, 158, 1568-1578.

Kilpatrick, D. G., Koenen, K. C., Ruggiero, K. J., Acierno, R., Galea, S., Resnick, H. S. et al. (2007). The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. American Journal of Psychiatry, 164, 1693-1699.

Low, N. C., Cui, L., & Merikangas, K. R. (2008). Specificity of familial transmission of anxiety and comorbid disorders. J.Psychiatr.Res., 42, 596-604.

McCarthy, M. I., Abecasis, G. R., Cardon, L. R., Goldstein, D. B., Little, J., Ioannidis, J. P. et al. (2008). Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat.Rev.Genet., 9, 356-369.

Micco, J. A., Henin, A., Mick, E., Kim, S., Hopkins, C. A., Biederman, J. et al. (2009). Anxiety and depressive disorders in offspring at high risk for anxiety: a meta-analysis. J Anxiety Disord., 23, 1158-1164.

Norrholm, S. D. & Ressler, K. J. (2009). Genetics of anxiety and trauma-related disorders. Neuroscience, 164, 272-287.

Pauls, D. L. (2008). The genetics of obsessive compulsive disorder: a review of the evidence. Am.J.Med.Genet.C.Semin.Med.Genet., 148, 133-139.

Ravindran, L. N. & Stein, M. B. (2009). Anxiety Disorders: Somatic Treatment. In B.J.Sadock, V. A. Sadock, & P. Ruiz (Eds.), Kaplan and Sadock Comprehensive Textbook of Psychiatry (9th Edition. ed., pp. 1906-1914). Philadelphia, PA: Lippincott Williams & Wilkins.

Smoller, J. W., Gardner-Schuster, E., & Covino, J. (2008). The genetic basis of panic and phobic anxiety disorders. Am.J.Med.Genet.C.Semin.Med.Genet., 148, 118-126.

Strug, L. J., Suresh, R., Fyer, A. J., Talati, A., Adams, P. B., Li, W. et al. (2010). Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Mol.Psychiatry, 15, 166-176.

Wendland, J. R., Moya, P. R., Kruse, M. R., Ren-Patterson, R. F., Jensen, C. L., Timpano, K. R. et al. (2008). A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder. Hum.Mol.Genet., 17, 717-723.