The genetic variant was 5-HTTLPR. It's a length variant in the gene coding for the serotonin transporter protein (5HTT) which the target of antidepressants like Prozac. There are two flavors of this variant, short and long.Many studies have shown that the short ("s") variant is associated with a high risk of getting depression in response to stress - but then last year a large meta-analysis of all the evidence concluded that there was in reality no link. Bummer.
Now another team of researchers have done a new analysis of the 5-HTTLPR & stress & depression data and they claim that there is a link after all: hooray! So who's right? I'm not sure, but the new paper raises many questions.
The new paper puts together the results of all 54 studies which have looked at this gene in the context of depression, caused by any kind of stress. The authors were intentionally liberal in their inclusion criteria: studies in any population were OK, for example they included people with Parkinson's disease or heart disease.
They say that this is the main difference between the present work and earlier meta-analyses that found no link. The famous 2010 paper, for example, only included 14 studies because they only considered certain kinds of stress.
Anyway, the short variant is associated with depression after all, across all of the studies. They extracted the p values from the results of all previous studies, and took the average of those, weighted by the sample size. They found a very significant association: P=.00002.
Here's all the results. Each square is a study, the further to the left, the more strongly they found an association. Bigger squares mean larger studies. As you can see, most studies found a link but the three largest studies - which were much larger than the others - found none. Hmm.In terms of specific kinds of stress, they found strong evidence that "specific stressors" (like medical illness), and childhood trauma, were associated with more depression in s-allele carriers. However, in the studies on "Stressful Life Events", which is a broad category meaning pretty much anything bad that happens, the evidence was weaker. The previous meta-analyses only considered these studies.
Ultimately, I think this analysis should remind us that the issue of 5HTTLPR is still "open", but I have concerns about the dataset. The fact that larger studies seem less likely to be positive is a classic warning sign of publication bias.
The authors do consider this and say that they calculate that there would have to be over 700 unpublished, negative studies out there, in order to make the overall data negative. They also find that you could ignore the smallest 45 studies and still find a result. But still. Something doesn't feel right. Maybe I just have the wrong 5HTTLPR variant.
Karg K, Burmeister M, Shedden K, & Sen S (2011). The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited: Evidence of Genetic Moderation. Archives of general psychiatry, 68 (5), 444-54 PMID: 21199959
11 comments:
Great blog: it does a great job at shaking the seemingly unshakable.
Long live the doubts!: for they make us more curious and not so closely certain.
When complexities outpace human capacity one sees patterns were they are not.
I guess we could class this in the category: watching clouds to see a figure.
Logically there should be a genetic basis for a widespread affliction whatever it may be.
Odds are against the same affliction being seen across cultures, social classes, gender and age just by pure coincidence.
But in view how the expression of one gene can set off a whole set of other expressions which in turn can tune down or up the original signal finding 1 single genetic cause will next to impossible.
This is exactly why meta analysis is bunk.
I'd love for you to do a post on the pitfalls of meta analysis...
Funny you should say that. John Ioannidis has just done a paper on that: http://dx.doi.org/10.1016/j.jclinepi.2010.12.012
It is on my "to blog" list.
The only issue i have, although i agree with the general point that metastudies stink, is that Ioannidis's paper is in itself a kind of metastudy of metastudies. But he's still the best we have to lay bare the connivances of the medical/pharmaceutical industry.
The money line in the abstract states: "we found strong evidence for an association between the s allele and increased stress sensitivity in the childhood maltreatment (P = .00007) and the specific medical condition (P = .0004) groups of studies but only marginal evidence for an association in the stressful life events group (P = .03)."
Perhaps there is a distinction between "psychological trauma" and "stress" with the s allele only relevant to the former, and the existence of any signficance in the stressful life events and s allele result may be a product of a subset of psychological trauma cases within the group of stressful life event sufferers.
One wonders if there might be a similar issue on the depression diagnosis side as well. Some of the depression drug studies, IIRC, have noticed differences in effectiveness on severe and less severe depression cases.
Perhaps there is one etiology mediated by the s allele that leads from psychological trauma to severe depression, and another that is not from stress to moderate depression.
I think it's clear that we ought to question the validity of this study... I mean, it's really a forgone conclusion that they would find an effect, given that they literally had almost no exclusion criteria.
And as another point, I really don't know why we ever thought that depression could be narrowed down to individual susceptibility genes. This really has been the tale of genetic studies on just about every complex mental disorder and illness: individual genes, even when considered in association with environmental factors, rarely account for complex traits. Until these studies start accounting for a large number of susceptibility genes--and, preferably, actual protein expression levels--it's really unlikely that we'll see much headway on the treatment front.
The amusing thing about this debate over 5HTT is that whether it is or isn't true probably has zero impact on anything important (such as development of novel antidepressant treatments) because we already have SSRIs.
One of my concerns about psychiatric research is that there is a lot of focus on the basic science to an exclusion of research on anything useful. Everyone talks a good game in their research proposals about how it is going to lead to new knowledge and novel treatments but it seems to me that is almost never the case - most basic research is an academic exercise conducted for purely intellectual curiosity.
Re: the Ionnidis article, I think this sums up its not exactly earth shattering conclusions:
"Most meta-analyses with nominally significant results pertain to truly nonnull effects, but exceptions are not uncommon. The magnitude of observed effects, especially in meta-analyses with limited evidence, is often inflated."
Or, publication bias in meta-analysis, what ya gonna do?
Although I do have serious reservations about meta-studies of meta-analysis because, for example, updated meta-analyses (like the ones studied by Ionnidis) are not a randomly selected subset of all meta-analyses performed, but rather there is a reason why they are subsequently updated (and further trials performed) so you cannot necessarily draw wider conclusions about meta-analyses in general.
A more valid approach would be one that is actually widely performed, to show how effect estimates change over time (simulating 'real time' meta-analysis as each new study is published) which also shows that effect sizes tend to decrease as further studies are published over time. Something that is almost certainly due to publication bias and inflation of effect size in early positive but small trials.
This doesn't mean that meta-analysis is a waste of time, the alternative is to just rely on a gut impression of the clinical trial literature, which is usually even more massively skewed by publication bias.
And someone will do another meta-analysis and the effect will disappear! Gotta love the science! Here one minute, gone the next, only to re-appear,and then be gone again! Kind of reminds me of all the antidepressant medication studies.
Thanks for your article, really useful information.
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