caspi

Your genetic info -- not free, easy, or clear

ddobbs — Thu, 01 Apr 2010 09:03:53 +0000

Your genetic info -- not free, easy, or clear

After I wrote in my Atlantic article about getting my serotonin transporter gene assayed (which revealed that I carry that gene's apparently more plastic short-short form), I started getting a lot of email â several a week â from readers asking how to have their SERT gene tested. This led to an interesting hunt.

It was a hard question to answer. I couldn't just tell people to do what I did, for a psychiatric researcher/MD I'd known for years, who specializes in depression and serotonin, had done mine as a sort of favor to science and journalism. That researcher also stood by, had I needed it, to offer counseling and more information about the result's implications â an important point.

Obviously I couldn't pass that researcher's name out to several dozen strangers. Yet the readers who wrote wanted the information for the same reason I did: They wanted to know whether they had a genetic variant that by the conventional reading simply increased your risk of depression, but by another reading â the hypothesis explored in my article â conferred a broader sensitivity to experience, which can be a good thing.

As I well knew, this is powerful information. It opens a big box with lots of compartments. Those compartments hold things like the recently raised (but far from settled) question of how solid a connection the S/S variant holds to depression. They hold the question of how a person might interpret the results, and whether they have the emotional, intellectual, and social assets to make the most of the information; as well as the whole pile of broader issues raised by the growing availability of spitomics.

Challenging territory. Yet in this case the biggest challenge my serotonin-curious readers encountered was just getting the test in the first place. For try as we might, we could not find a place to run a SERT assay. People would try various companies, such as 23andme, and report back that they'd struck out. I suspect this is because the lawyers at such companies likely advise against giving test results regarding mental illness to people whose very interest in the test suggested they might be prone to depression.

So I started suggesting the long route to my solution: Try to find a psychiatrist at a research university interested in serotonin and convince that person, with your doctor's help if need be, to run the assay. That too proved elusive.

But one particular reader (I'll call her Natalie, which is not her real name) refused to give up. She wrote me back in early February saying her therapist had given her the Atlantic article, and she wanted to know her SERT type. She suspected she was indeed S/S. So off she went a-hunting. She struck out with the major gene-testing services, but after several back-and-forths and dead ends, seemed very close to getting an assay done at a nearby research university. The psychiatrist there, having read the article, seemed game, and set up an appointment. When she visited him, medical history in hand, the psychiatrist "was conscientious, thorough, and very interested, but understandably cautious." She liked him. But he ultimately declined to prescribe the test. He told her, she wrote me, that

the general body of research was inconclusive and contradictory, [and] professional organizations (such as AMA for geneticists) advised against it. Presently doing the test "would do more harm than good" and I should check back every few years when perhaps the test would provide concrete information. I think he was highly ethical and also covering his ass.

I think she's right. It's easy to understand this doctor's response. Some have lately questioned whether the S/S confers risk. Even if you believe the S/S does confer risk (and the field is very much split on this), do you want to deliver that news to someone whose depression might lead them to take the news badly? The view of S/S as a 'risk' gene rather than a plasticity gene remains the prevailing paradigm. And it seemed to drive the no-test decision Natalie and other readers encountered âeven though, in Natalie's case, she had shown the researcher the article and told him she was viewing the potential results as a sign of sensitivity rather than just risk.

But just at this point, where the road seemed to peter out completely, Karen found, hidden in the weeds, a lab that would run the SERT assay. Why would they do it?. Because, they said, "Researchers have found that mutations in some genes specifically change how effectively SSRIs may act," and that in the SERT gene, "[p]patients who have the short allele are less likely to respond to SSRIs or may take longer to respond."

This is true â but only in some trials, but not in others. The data on the SERT gene's effect on SSRI response is mixed. Yet it's interesting that the company lean on this to offer the test.

No matter to Natalie. She's primed to see what she's got. "I can tell you right now I am hoping for the short-short," she says. "The process is in the works for me, so now we shall see. This is so much fun."

I obviously think people should be able to get this information â though they should get it with some informed counseling. But this entire hunt, and the various reasons to give or not give people this information about themselves, raises a mess of intriguing and often slippery issues. The genetic testing industry, and the understandable excitement about the potential and power of genomic information, generally assumes that we either don't know a gene's meaning or that we do. But the case of the SERT gene shows that a gene's meaning can be far from certain -- and that it can change substantially as researchers do more work on it and view the existing data from different angles. Here we have a gene variant â possibly the most prominent in behavioral science, certainly in psychiatry â that, depending on whom you ask, is bad news, no news, or news whose meaning ... depends.

As the genome's parts come into view, their meaning sometimes shift. How will the fast-spreading, fast-growing gene-information industry handle this movement? How do you give people advice about a gene whose meaning seems to be changing? How, say, would a pre-conception gene counseling service, something along the lines of Counsyl, handle this dilemma?

This isn't something we'll figure out in a few blog posts; it's something the industry and the broader genomics community will need to consider carefully over the next few years, even as it rapidly grows. I'll be talking about and leading discussions on these questions at the upcoming GET conference in Cambridge and then at a closed workshop at the Institute for the Future â a start. Your own ideas â as well as pointers to other explorations of these questions â are most welcome in the comments or via the Twittersphere.

ddobbs Thu, 04/01/2010 - 05:03

"Your genetic info -- not free, easy, or clear."

And not useful, either.

They know the gene for Rett syndrome. Anything useful come of that yet?

They know the gene for Huntington's disease. Got a cure yet?

They know the gene for the familial form of ALS a/k/a Lou Gehrig's disease. Even though the familial form is only around 10% or so - nothing useful there either.

And so it goes.

They find "the gene for" whatever it may, but it does absolutely no good. They have, as the British like to say, the wrong end of the stick. Disgusting.

I disagree with this drama. I am old enough to remember when we didn't have the tech to know the sex of an unborn child. And then we did and then we had the same kind of discussion you and others like to engage in. As hard as it is to believe, people thought it would be "hard to handle" and they would need counseling. Scenarios were given such as, "Suppose this is the 4th child and all are girls and dad wants a boy. He might leave. Mom will get depressed and abandon the kids." It is the same kind of paternalistic, only we of the intelligentsia can handle this theme. Then one day everyone knew the sex of the unborn and the world went on spinning and dads didn't leave and moms didn't get depressed and run away.

It really isn't hard to explain: 1. This is not a given. 2. You control the eventual outcome because genes and environment are both important. 3. The only information this gives you is a roadmap for what actions you might take, what food you might eat, or how many music lessons you need to develop perfect pitch. 4. New information is being learned every day and this result could be overturned. 5. Check the following website for updates.

And yes - this info is useful. Even for HD or breast cancer. Suppose there was an alternative to the inevitable? There is in many cases. I'm taking low dose naltrexone not only for the chronic immune illness I have (and which is has stopped completely) but also because there is evidence it acts prophylactically on cancer. And it is being looked at for HD since it has been hugely successful in MS. (This isn't junk science. Clinical trials at Stanford, NIH, Penn State will show that.)

I'd say those who diss this and say, "no use" are pessimists who aren't thinking or curious and live in the past. Science moves forward by pushing boundaries. Don't shove it into the box labeled,"You need counseling." That's not helpful. And if you can't embrace and see the future without the sky falling in, find a way to prop it up instead.

I believe in the people and their power to learn. But they won't learn if they are told they can't be taught by those that clasp the knowledge close and will not teach or share.

Shamans see the coiled snake all the time and teach the tribes what life lessons it gives them. We call it DNA. It has much to teach and we have much to learn but we can't be afraid of its power and put it on a pedestal and keep it from the people.

Sit vis vobiscum

Why should people not be able to find out their genetic make up if they wish? Failure to allow open access to information moves science into the realm of religion and creates more problems than it solves.

Interesting articles you have very informative though for nobrains it seem hard to understand ! though i already read your articles over and over lol! maybe its not me ;) but you have interesting articles !

I find this very intriguing, thank you for the article, David. I have felt for years that I was prone to depression simply because both of my parents have had it. To know that there might be a gene out there that can prove just that boggles my mind. I would love to be tested for the S/S, but I doubt that insurance would cover it and I don't have the money to pay for it. While I understand that there are many facilities that won't do the procedure, do you suppose that there might be one that does? Where did Karen go?

Key paper in depression genetics disputed

purepedantry — Wed, 24 Jun 2009 07:00:58 +0000

Key paper in depression genetics disputed

I wanted to draw attention to a new paper in JAMA recently because it reveals a lot about how conditional most of the statements we make in behavioral genetics are. Every time you hear a news article that says, "Gene for depression found," I want you to think about this case.

Risch et al. performed a meta-analysis on 14 studies that were looking at Serotonin Transporter (5-HTTLPR) genotype and number of stressful life events. These two factors were related to the subsequent risk for developing clinical depression. Their analysis found -- contrary to a very well known study, Caspi et al. -- that there was no association between genotype for this gene and depression risk and no significant interaction between genotype and number of stressful life events.

I think this case is a good example of why we should be skeptical of behavioral genetics studies reported in the news until they have been replicated repeatedly.

Back in 2003, Caspi et al. performed a longitudinal study on roughly a thousand children that looked at the number stressful life events that had happened to them. Stressful life events could include things like losing a job or your parents getting divorced. Then at the age of 26 each of the participants in the study was evaluated for clinical depression according to standardized criteria. Samples were also taken for genetic testing particularly at the gene for the serotonin transporter, 5-HTTLPR. (The choice of the gene to evaluate made sense because many of the drugs we use to treat depression modify activity of the serotonin system in the brain.)

The authors asked: how do a particular genotype of the serotonin gene and stressful life events interact to influence depression risk? Does having a certain genotype PLUS several stressful life events increase your risk?

Their results were stunning primarily because they so clearly illustrated the concept of a gene-environment interaction: the idea that neither your genes nor the environment is sufficient to cause depression; rather, depression results from a confluence of both factors.

Here is an example of their data (from Figure 2 of the paper):

The results show risk of depression (in percent, from ages 18 to 26) as related to whether the participant was mistreated as a child (from the ages of 3 to 11). The participants are broken up according to whether they have two of the short forms of the serotonin transporter gene (s/s), are heterozygotes for the long form for serotonin transporter (s/l), or have two copies of the long form (l/l).

In the absence of childhood mistreatment, there is no difference between the three genetic groups with respect to depression risk. Likewise, if you possess two copies of the long form (l/l) childhood mistreatment does not increase your risk. However, if you possess two copies of the short form (s/s) AND you were subjected to childhood mistreatment, your risk of depression doubles.

This and other data was used to argue that what determines whether an individual will get depression is a gene-environment interaction. Genes confer risk for depression, but only in the presence of stressful life events does a particular genetic makeup manifest.

I want to make something clear through all of this: Caspi et al. is an extremely well done paper. Up until reading this meta-analysis, I considered it the benchmark for these kinds of studies. Even realizing that the findings may have been a false positive, I still respect it. So I don't want to suggest that I am trashing this work.

After Caspi et al., there emerged many other papers that attempted to find gene-environment interactions in the similar way. Primarily this was because Caspi et al. addressed a problem that had been quite prevalent in behavioral genetics: small and non-reproducible effects.

A common problem in studies attempting to relate genetics with a particular behavior is that a particular genotype might only confer a very small risk. Also, behavioral genetics studies are notoriously difficult to replicate. Say you find a significant relationship between gene A and depression. Then you go and try and replicate that finding in another population. A lot of the time, you will find that it is no longer significant in the new population. Sometimes that is because it was a weak correlation, and you don't have enough people in the study. Sometimes it is because in the new population, the genetic background for their other genes masks the effect of gene A on depression. (This is called an epistatic interaction.)

The point is that behavioral genetics studies were dealing with a problem of reproducibility and small effect sizes. Caspi et al. demonstrated a way to identify more significant effects. If you can show that a subset of your population with a particular environmental history, there is an even greater association between the disease and their genotype, you can argue that the interaction between the two potentiated the effect of the gene. It also explains why there was so much trouble finding a significant gene-disease correlations: there were aspects of the population that you were missing.

If you think about it, the concept of a gene-environment also makes a great deal of sense. Let's set aside the fact that biological systems show these all the time for physical traits. (It is a core principle to our understanding of evolution.) An individuals behavior is the consequence of many, many genes and many, many environmental interactions. To say that a single gene could result in a behavior, we would have to assume that it was relatively robust to a variety of environments that the individual might experience -- that regardless of environment, the person would still show the behavior. But this argument belies the extreme variability that is present in human behavior. Even among identical twins there is a great deal of variation in personal preference, environment, and hence the risk for disease.

My point is that you can't take too much of an issue with Caspi et al. for arguing for the existence of gene-environment interactions in producing behavioral outcomes because they make too much sense in light of what we already know about biology.

The problem, unfortunately, came in trying to verify the results of their work.

Risch and colleagues performed a meta-analysis using the original data from 14 studies that had attempted to replicate the findings of Caspi et al. These studies also looked at the roles of stressful life events, genotype at the serotonin transporter gene, and the resulting depression risk. In contrast to the earlier work, the authors found no relationship between serotonin transporter genotypes or the interaction and depression risk. The only significant predictor they found was the number of stressful life events:

In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data.

Note that this meta-analysis was performed on about 14 thousand participants from other studies. Hence it has a much greater statistical power than the previous study.

What do we make of this conclusion? How is it possible that such a well-constructed study -- that had become a model for a variety of other studies -- ended up being wrong?

Well, first of all, I should note that the lead author from the original study does not necessarily agree with the findings of this meta-analysis. From the NYTimes coverage:

Others said the new analysis was unjustifiably dismissive. "What is needed is not less research into gene-environment interaction," Avshalom Caspi, a neuroscientist at Duke University and lead author of the original paper, wrote in an e-mail message, "but more research of better quality."

I would say a couple of things:

1) No one in the coverage I have read of this story -- including the authors of the meta-analysis -- is disputing that gene-environment interactions exist for behavioral phenotypes or that these studies NEED to continue being done. In fact, most of the coverage of this study has shown an very interesting doublethink, denying the accuracy of the original Caspi study findings while singing the praises of its theoretical basis.
2) This is exactly the type of back and forth that we should expect from behavioral genetics studies. We should have a great deal of reticence when we read about studies like this in the news.

Behavior is affected by many, many genes. No one ever believed that just one gene was going to explain all of depression or any other mental illness. This is primarily why the effect sizes in these studies are so small: because behavior is so polygenic. Furthermore, when you are dealing with small effect sizes in complex systems, you have to prepare yourself for the possibility of sampling error. Caspi et al. was not a small study, but it also should surprise us that an analysis of a larger population yielded different results.

The point, I guess, is that we can simultaneously dispute the relevance of this particular gene, the serotonin transporter, in affecting depression risk while still believing in the concept of a gene-environment interaction.

We just have to be very, very careful when we assert with certainly the association of a particular gene. Results that look too good to be true often are.

Hat-tip: NYTimes

purepedantry Wed, 06/24/2009 - 03:00

The (Illusory) Rise and Fall of the "Depression Gene"

ddobbs — Wed, 17 Jun 2009 09:01:55 +0000

The (Illusory) Rise and Fall of the "Depression Gene"

Big psych news of the day is that a big JAMA study debunked the "depression gene" -- that is, this big new study (by Risch et alia, in JAMA, today) found that, contrary to a famous earlier big study (Caspi et alia, in Science, 2003), the short ("bad") form of a particular gene called 5-HTT does NOT make a person more vulnerable to depression. Or, to flip it:: Caspi 2003 had found that having a short version of 5-HTT, which affects processing of serotonin, put someone at more risk of depression if they experienced (as adults) repeated stressful life events. Risch 2009, crunching data from a bunch of studies (including Caspi 2003) to ask the same question -- Does the short version of 5-HTT make you more vulnerable to depression if you suffer stressful events as an adult? -- found the answer was No.

The headlines are predictable enough, "Sad News for Depression Gene" being perhaps the funnest.

But wait; not so fast. Has an empire crumbled here? A hypothesis evaporated?

You need only look at this briefly, I think, to see that the question addressed by both papers is fairly limited, and does not, crucially, cover variations in how early life experiences might amplify any risk conferred by the short 5-HTT allele. (Caspi & Moffitt clearly ~~did not include such events in theirs~~ excluded such early experiences from some of their analyses, and in fact took measures in some of their measures, such as removing from analysis anyone who suffered depression before age 21, that would be likely to exclude some people who suffered particularly rough early years.. And unless I missed something in reading the Risch paper, it too makes no effort to look at early experience in particular -- and, since it pulled Caspi's data from Caspia, would reflect the same possible filtering out of such early-onset depression cases.)

This failure to look at early experience is important, for amid the very large body of studies of gene-environment interactions and how genes and experience might combine to heighten risk of depression, the starkest effects have been found in studies that look at very early experience. Those studies, in both animals and humans, appear to find that very stressful early years -- tumultuous times, lousy parenting -- seem to heighten the sensitivity of genes such as 5-HTT that have been more broadly associated with risk of depression and other problems. The most significant activator of these "risk" genes, in other words, seems to be very early experience; and the Risch paper -- for perfectly good reasons, as it is seeking to answer a simpler question -- doesn't address those studies at all.

So what we have, really, is a big paper -- Risch 2009 -- that appears to refute another big paper (Caspi 2003), that is but one leg supporting a broad model of gene-environment interaction as a risk for depression. So what happens if you kick out that leg? Does the house fall? Not if it has a bunch of other legs under it. In fact, it may be that kicking out that leg merely will show you that the leg was in fact an early bit of scaffolding, and that the house will stand quite well without it.

The Risch paper will doubtless spur a lot of critical looks at the body of work on gene-environment dynamics in psychiatry and behavior. This can only be a good thing. But to declare dead both the "depression gene" and an entire model of risk seems rather premature.

Not that that's stopping the press. The press in general is rushing to declare, in sensational fashion, its earlier simplistic sensationalism erroneous, and I've little doubt that many lay readers will conclude, Hmm, that business about genes putting you at risk for depression (or other ailments) is hokum.

That said, among the most valuable takes so far are Ben Carey's at the Times (which acknowledges lightly some of the caveats I spell out); a short piece at the Wall Street Journal Health Blog; and Constance Holden's at Science.

ddobbs Wed, 06/17/2009 - 05:01