Last year, the world of psychiatric genetics was rocked by the news that a highly-studied gene, believed to be associated with depression, wasn't in fact linked to depression at all.
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
