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.
