Knowing One’s Genome: Are We Ready?

There are many reasons to worry about what will be done with personal genetic information, once obtaining it is easy and inexpensive. An editorial in Scientific American worries what companies like 23andMe will do with it.¹ We in psychiatry wonder what patients and families will do with direct-to-consumer genetic testing. For even though 23andMe can no longer provide extensive genetic information since its cease-and-desist order from the FDA, one need only take the data the site still provides and hand it to another company (such as Promethease) to receive detailed information on one’s own genome.

For instance, take the serotonin transporter (SRT) gene length difference, originally described by Caspi et al.² As most readers will know, this gene has two allelic forms: one long, one short (a moderate oversimplification). Since everyone gets a version of this gene from each parent, there are 3 genetic possibilities: 2 longs, 2 shorts, or a long and a short. In the study, the short allele was associated with an increased risk of depression and suicidality.

[[{"type":"media","view_mode":"media_crop","fid":"40055","attributes":{"alt":"genomes","class":"media-image media-image-right","height":"212","id":"media_crop_7029530048722","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4052","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"©foxterrier2005-Shutterstock","typeof":"foaf:Image","width":"247"}}]]Using services like as 23andMe or Promethease, patients can know their own SRT alleles. What will they do with this information? The SRT polymorphism is one of the most well studied genetic variations affecting mood disorders. Can we help patients understand the implications of their results? (Whether, as an editorial accompanying the Caspi study put it, one got “the short end of the allele”?)

Unfortunately, replicating the Caspi finding has proven complex. First came a widely publicized meta-analysis in JAMA suggesting the finding was not confirmed.³ Now comes another meta-analysis that incorporates multiple subsequent research studies.⁴ The authors found that all relevant studies to date, taken together, confirm a significant relationship between the short allele and increased risk of depression (p = 0.0000009). However, they also note that 25% of studies did not find this association, and 4 studies found the opposite.

What is going on?
The key may lie in another finding from the Caspi study: the gene difference only manifests itself in increased depression when subjects had also experienced significant childhood maltreatment.² This finding too has been replicated numerous times,⁵ but how one defines maltreatment, and the age at which it occurred, may account for some of the variation in the many studies since Caspi et al.

The new meta-analysis keeps the SRT polymorphism alive as an area worth study. For example, some research has shown that in the presence of a particularly benign and supportive childhood, the short allele may actually confer benefit relative to the long allele.⁶

Meanwhile, what should clinicians tell patients and families about genes and mood disorders? Perhaps this: One cannot know anything meaningful at this stage based on your genes for the serotonin transporter, and that is the one we understand best. Be cautious if anyone tells you otherwise. But we do know one thing from the research on that gene: doing your best to insure that a child does not experience physical or sexual abuse while growing up will have at least as much impact as the genes she carries.

Disclosures:

Dr Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore. He is the Bipolar Disorder Section Editor for Psychiatric Times. [full bio]

References:

1. Seife C. 23andMe Is Terrifying, but Not for the Reasons the FDA Thinks. Scientific American, 2013. http://www.scientificamerican.com/article/23andme-is-terrifying-but-not-for-reasons-fda. Accessed July 31, 2015.
2. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386-389.
3. Risch N, Herrell R, Lehner T, et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA. 2009;301:2462–2471.
4. Sharpley CF, Palanisamy SK, Glyde NS, et al. An update on the interaction between the serotonin transporter promoter variant (5-HTTLPR), stress and depression, plus an exploration of non-confirming findings. Behav Brain Res. 2014;273:89-105.
5. Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry. 2011;68:444-54.
6. Belsky J, Jonassaint C, Pluess, M et al. Vulnerability genes or plasticity genes? Mol Psychiatry. 2009;14:746-54.