Debunking myths on genetics and DNA

Sunday, December 18, 2011

Enough with OXTR associations. Here's what I really want to know.

EDIT: After reading the post, please check out the comments. Luke, from Genomes Unzipped, helped me understand the matter better, so don't miss his comment!

Another OXTR paper came out in PNAS, the third since September. OXTR is the gene coding the oxytocin receptor. Given the benefits of oxytocin (dubbed the "love hormone"), people have focused on studying this gene and, in particular, possible associations between a common OXTR polymorphism, rs53576, and various behaviors:
"One SNP in the third intron of OXTR has emerged as a particularly promising candidate in recent studies on human social behavior: rs53576 (G/A). In recent studies, the A allele of rs53576 has been associated with reduced maternal sensitivity to child behavior, lower empathy, reduced reward dependence, lower optimism and self-esteem, and, in men, negative affect. Moreover, the A allele has also been associated with a larger startle response and reduced amygdala activation during emotional face processing. Associations have also been reported between other variants of OXTR and amygdala volume, risk for autism, the quality of infants‚ attachment bonds with their caregivers, attachment anxiety in adult females, and autistic-like social difficulties in adult males [1]."
This study in particular [1] recruited 194 individuals and found an association between the SNP in question and the way the participants reacted to positive feedback during stressful situations. They did this by measuring cortisol responses to stress based on the fact that psychosocial stress increase the levels of salivary cortisol. In AA carriers they found that these levels remained unchanged whether they received the support or not. The researchers conclude:
"Physiologically, it can be speculated that oxytocin released in the context of social support influences stress processing systems via oxytocin receptors in hypothalamic‚ limbic circuits. One likely important site of action is the amygdala, critically involved in basic emotional processing and the regulation of complex social behavior."
I confess I've been eagerly following these OXTR studies and indeed they make a great story. There's a part, though, that puzzles me, and the reason why I'm discussing this paper today is to ask a general question. If you're an expert on these things I welcome your input.

I understand these are important studies because, despite some recent criticism, they are still getting published, and PNAS, as we all know, is one of the top science journals out there. However, the thing I don't understand is that rs53576 is a silent SNP. That's actually not surprising, because, as it turns out, most common polymorphisms are silent. What is surprising, though, is that most silent SNPs are non functional, and none of these studies I've read seems to raise the question. Let me explain.

Rs53576 sits in an intron, a part of the gene that is not transcribed into RNA and hence, in this case, does not affect the way the oxytocin receptor is made. In the analogous studies we do in my group, which are NOT on humans, we look for non-silent mutations because those are the ones that affect the crystal structure of the protein. We then look at what differences in structure these mutations yield to explain how more or less molecules bind to the protein, and this how we explain the observed effects. If rs53576 were a non-silent mutation, I'd know where to look to explain these associations: I'd look at how the SNP affects the crystal structure of the receptor, the hypothesis being that the oxytocin receptor in AA carriers binds less oxytocin than GG carriers (or something along those lines, I obviously don't know the details of this particular receptor). But rs53576 is silent. Hence, if the associations are real, there is something else going on. So, why hasn't anybody raised the question of what else is going on here?

The first thing that comes to mind is that this particular SNP could be in linkage disequilibrium with some other SNP or groups of SNPs which, instead, are non-silent. We tend to inherit polymorphisms in groups, and so if rs53576 comes in the same "package" (they're called haplotype blocks) as some other functional SNP, then rs53576 is NOT the causal SNP for all these effects and we should really be looking elsewhere. The way to find out, of course, is to repeat all these studies with whole genome data. But, it could also be an epigenetic change or a post-transcriptional modification occurring between the primary transcript RNA (which contains both introns and exons) and the mature messenger RNA (which then yields to the protein). The positions of introns can indeed affect the translational properties of the RNA, and that's what yields to the so-called "functional intronic SNPs." The fact that intronic polymorphisms can be functional is extremely interesting, and in fact, last year, this study showed that one particular SNP found in one intron of GH1, the growth hormone, could indeed be functional.

Whatever it is, at this point, isn't it more interesting to investigate what's going on with this SNP at the molecular level rather than looking at all these association studies which may or may not be true?

[1] Chen, F., Kumsta, R., von Dawans, B., Monakhov, M., Ebstein, R., & Heinrichs, M. (2011). Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans Proceedings of the National Academy of Sciences, 108 (50), 19937-19942 DOI: 10.1073/pnas.1113079108

Photo: Fall colors along the Rio Grande. Shutter speed 1/40, F-stop 5.6, ISO speed 100, and focal length 85mm.


  1. I've always wondered if intronic SNPs had more to do with RNAi downstream gene regulation. It doesn't fit with our understanding of RNAi processing but it wouldn't be the first time that RNA messed with our notions of gene expression.

  2. Thanks. I hope the post doesn't sound snarly, I'm just surprised these studies don't mention these things in the discussion. To me it's the real puzzle. How can you infer all these pathway correlations if we don't really know how the SNP affects the receptor?

  3. There have been a lot of work recently functionally tying down complex trait effects - you'll see a lot of it published in 2012. It looks like the majority all common associations to complex human traits do not change the protein sequence. The main driver of common human complex trait variation is regulatory, not protein coding. We have known that a lot of complex trait genetics is non-coding for a number of years now, since the first GWAS starting rolling in, which is why no-one makes that much of a big deal about non-coding associations these days.

    As for what these variants actually do, a lot of them seems to affect DNA binding events - transcription factor/microRNA binding sites etc, but a whole host of other things are going on too. This OXTR intronic variant doesn't appear to be in LD with any coding variants, but does seem to lie within a region that is methylated, so it could be messing up epigenetic marks.

  4. Thanks so much for this comment! Okay, I get it, so my view was kind of limited... so then, once again, it boils down to epigenetic marks and the fact we still don't quite understand them...

    Many thanks for explaining this to me!

  5. One small addition: no one makes a big deal of it, but I think they should. I think the words "causal variant" should be used with a grain of salt. Yes, it could be regulatory, like you say. But we haven't proven that yet. It could be that we are seeing more spurious relations than we think we are. The genome is way more complex than we think it is. It is also true that RNA affects traits in ways that we don't fully understand, so. Anyways, all this to appeal for more caution in making conclusions, that's all.


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