Thursday, June 18, 2009

Myth of the Depression Gene

There never was a single "depression gene", and those patting themselves on the back because of the ceremonial defenestration of that straw man are fooling themselves.

Yes, a new meta-analysis in JAMA (Risch et al., 2009) found that a variant of the serotonin transporter gene (the 5-HTTLPR polymorphic region) is not linked to an increased risk of depression, either alone or in combination with stressful life events. This study examined 14 prior papers, including the now-maligned article by Caspi et al. (2003) in Science.

A depiction of the organization of the serotonin transporter showing the 5HTTLPR region and the positions of several SNPs. Adapted from Heils et al, 1996 and Lesch et al, 1996 by the Genotyping Lab at the University of Colorado.

Contrary to popular opinion, Caspi et al. never said that the single gene 5-HTTLPR is the "prime driver" of depression. Instead, they suggested that it moderates the effects of stressful life events on the risk of depression:
Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.
Caspi et al. (2003) also said the following:
  • Evidence for an association between the short promoter variant and depression is inconclusive. Although the 5-HTT gene may not be directly associated with depression, it could moderate the serotonergic response to stress.
  • Much genetic research has been guided by the assumption that genes cause diseases, but the expectation that direct paths will be found from gene to disease has not proven fruitful for complex psychiatric disorders.
  • Until this study's findings are replicated, speculation about clinical implications is premature.
And the findings did not replicate, which was always a possibility in their view.

Another issue -- the importance of early life experience -- is raised by David Dobbs in The (Illusory) Rise and Fall of the "Depression Gene":

. . .

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.)

But does anyone still believe that complex psychiatric disorders are caused by a single gene? I think not. The field of psychiatry genetics is littered with examples of "a gene for schizophrenia" and "the gene for bipolar disorder" that have failed to replicate. Even the most ardent proponents have become more circumspect about the search for genes that predispose one to specific mental illnesses.

Hey oncologists: where's "the gene" for cancer? Neurologists, have you found "the gene" for Alzheimer's disease yet? No? Why not? Because they're complex multidetermined diseases. Does that mean there is no role for genetic contributions to these disorders? Of course not! Here's an editorial by Thomas (2005) in Cancer Epidemiology Biomarkers & Prevention:
Thinking about biochemical pathways has become an increasingly important part of molecular epidemiology. The field is rapidly moving from evaluation of single candidate genes, one at a time, to consideration of entire pathways comprising perhaps dozens of genes and their environmental substrates, even multiple pathways that link up or compete in complex networks. Even in its simplest rendering, for example, dietary folate seems to be a protective factor for colorectal cancer and is involved in at least two distinct pathways... Many proteins critical in folate metabolism are coded for by genes with known polymorphisms. Alcohol and vitamins B6 and B12 also play a role in the folate pathway, and of course other pathways involving metabolism of heterocyclic amines, polycyclic aromatic hydrocarbons, bile acids, and nonsteroidal anti-inflammatory drugs might compete or interact with the folate pathways... To further complicate matters, there is evidence that folate may protect against early precancerous lesions but increase the risk of cancer in those with preexisting lesions.
Why should it be any different for bipolar disorder and major depression? Of course a person's life experiences and their environment influence whether or not they develop depression. Given identical circumstances, some people are more likely to become depressed than others. Why is that?

Clinging to the stubborn view that there is absolutely no biological basis for depression is just as preposterous as saying that stressful life events have no influence whatsoever on one's mental health. Get over it.


Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386-9.

Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR. (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA, 301 (23), 2462-2471.

Thomas DC. (2005). The need for a systematic approach to complex pathways in molecular epidemiology. Cancer Epidemiol Biomarkers Prev. 14:557-9.

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At June 18, 2009 3:48 PM, Anonymous Anonymous said...

Great blog.

At June 18, 2009 4:01 PM, Blogger The Neurocritic said...

Thanks. You made a good point, Dave.

One could do a separate post on the before-and-after headlines. Here's ScienceNOW:

Getting the Short End of the Allele
18 July 2003
Gene influences risk of depression after stressful events

Sad News for "Depression Gene"
16 June 2009
Analysis fails to find link between much-touted gene variant and depression

At June 21, 2009 7:46 AM, Blogger Finn Årup Nielsen said...

One of the first articles on the 5-HTTLPR argued for link to the personality dimensions 'neuroticism' and 'harm avoidance' (that have been linked to depression). This association has also been very much weakened by newer meta-analyses. (I put the references in Wikipedia) Though these cases make a mock of one-gene-one-disease claims I believe that rare familial Alzheimers may be linked to individual genes. Also for 'ordinary' Alzheimer the AlzGene meta-analysis odds ratio for the APOE gene is pretty high: 3.7. So to me that appears to be a myth.

At June 21, 2009 3:14 PM, Blogger Finn Årup Nielsen said...

Typo: It should have been "So to me that appears not to be a myth" or "it is a myth that is a myth..." :)

At June 21, 2009 5:13 PM, Blogger jonathan said...

I have mild autism, and it is probably the same for autism also, a combination of many genes found on autosomes and sometimes x-linked and lead to similar phenotypes.

At June 21, 2009 10:02 PM, Blogger The Neurocritic said...

Finn Årup Nielsen - The ApoE story seems to be complicated. Here's Schipper (2009) in a recent review of Apolipoprotein E:

"It is important to acknowledge that about half of E4 homozygotes do not contract AD by 90 years of age, and lack of the allele does not ensure immunity from the disease (Henderson et al., 1995). Thus, the apoE E4 gene or protein does not constitute a biological marker of sporadic AD and its utility as a routine AD diagnostic tool is minimal or nil (Hyman, 1998; Mayeux et al., 1998)."

Jonathan - I agree that autism is another good example.

At June 22, 2009 2:12 AM, Blogger Mariana Soffer said...

I always thought that is absurd to try to blame on a single gene (specially that we know we have many), a certain trait or expression of it that is obviously a complex thing.
Besides I think that is highly likely that the dna works like a kind of networks where one part influences other, and so on. And maybe there are even hierarchical connections which coordinate the basic ones.
They think they understand a lot about the dna, but I think they are missing a lot, just a couple of years ago they thought that the non coding dna parts where junk, and obviously it resulted that not.

At June 24, 2009 11:46 AM, Blogger Dr. Matthew said...

As a psychologist in the mental health field, I'm often frustrated by the lay "wisdom" that insists depression is purely biological, and leads many prospective clients to come in expecting immediate or automatic referral for psychotropic medications because depression is caused by a serotonin deficit.. right? In an ideal world, I'd require all depression researchers to read The Myth of Depression as Disease, by Leventhal and Martell. I don't think a person has to agree with every point in there (or in the literature as a whole) to acknowledge that the antecedents of depression may be predominantly environmental, and that changes to the context and environment may be preferable to a chemical "fix" (when, in fact, a successful "fix" occurs).

At June 26, 2009 10:15 AM, Blogger Finn Årup Nielsen said...

The Neurocritic - I agree that the ApoE story is complicated: That ApoE is not The Gene for late-onset Alzheimer. I guess I got carried away by the relatively high odds ratio - above 3 - in AlzGene. No other gene seems to get anywhere near. Also in the SczGene schizophrenia meta-analyses all genes seems to have ridiculous low odds ratio (i.e. near one). Doesn't that mean that ApoE is the only gene for any major neuropsychiatric disorder and disease where meta-analyses so far have revealed any 'large' association?

At July 29, 2009 11:28 AM, Anonymous Miek said...

Always the same... Just like in the 1800s with Galton: nature & nurture. The two are important. Not only the nature (genes, or better: multiple genes), but also the nurture (experiences). And not only nurture, without nature... That's also silly.

If we think, worry, cry, be happy, or whatever, we change the neurotransmitters (like serotonin), or the chemistry in our brains. Without brains (and chemistry), there's no thinking.
Or, if the chemistry in our brains has been changed (by our biology or our environment), our thinking will change. It's not 'or, or', it's 'and, and'.

We can change our chemistry in our brain bij changing our thinking (like psychotherapy), or by changing the chemistry (by medication).
The problem is that we aren't yet able to do that perfectly. Not by medication and not by psychotherapy. So, the best we can do for the moment when the depression is severe, is working on the two: psychotherapy AND medication.


At August 04, 2009 7:52 AM, Blogger 53nn said...

not nicely done...quite a lazy and apathetic confirmation bias. time for a new hobby, huh?

At August 05, 2009 12:17 AM, Blogger The Neurocritic said...

Perhaps I should take up your hobby: leaving trollish comments.

At January 04, 2011 8:43 PM, Blogger nooffensebut said...

You should update this post since the study you cite is now known to have been biased and inaccurate.

At January 06, 2011 3:52 PM, Blogger nooffensebut said...

Risch et al was a meta-analysis based upon a biased selection of studies. A new, more complete meta-analysis by Karg et al disproved their conclusion. Scientists have called upon the media to cover this correction.


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