Tuesday, January 26, 2010

The Yin and Yang of GWAS

It's fair enough to say that if it looks like a duck, and quacks like a duck, it must be alive and hence in principle you should be able to GWAS it (do a genome-wide association study) to discover its genetic basis. It would seem that, according to some scientist, somewhere, almost any trait you can name will be put under the GWASlight.

Today's Bulletin of the Shocking is the identification of a number of Y-linked genes. No, we're not talking about the male equivalent of girls' G-spots, the mythical Y-point. No, in this case the subject is non-western, specifically Asian, medicine: the Yin and Yang of life. How long is your Yin and how deep your Yang? It must be genetic, and they've now gone looking for it!

In what seems similar in spirit to Galenic medicine, of the Four Humours fame, JM Lee, a Korean physician in 1894 invented (discovered?) the Four-constitution medicine (FCM). Yin and Yang are, as we understand them, complementary opposites that contribute to individuals as wholes. These concepts are important in Asian philosophy, and have some connection to acupuncture theory, too. But we are far from knowledgable enough to describe, much less to comment on, this background.

In this quaternary view of nature, each individual's physical and mental traits lead to categorization, a Four-consitution type (FCT). You are either a GYN (greater Yin), LYN (lesser Yin), Greater Yang (GYA), or lesser (LYA). Given your score, clinical applications to everything including mental attitudes and food recommendations can follow.

Well, since it appears that your FCT is associated with personality, and you're alive, one can do GWAS from questionnaire-based phenotypes -- and this has now been done. 353,202 SNP markers were typed on healthy individuals in a 'genetically homogeneous population' of Korea. Looking for genetic variation in a homogeneous population seems strange, for starters, but let's let that slide.

A sample of 20 each from GYN, LYN, and LYA classified individuals were GWASed (they gave permission!). They couldn't find enough GYAs to include in this study. They then paired up individuals from two different groups, such as LYA-LYN, and in each of several such paired tests found GWAS SNPs that Yinned the subjects' Yangs, or Yanged their Yin, with statistical significance. They used all of the ready-made, off-the-shelf software that the profession routinely use to check for accuracy and aspects of statistical testing.

The result was that out of the 353,202 tested SNPs, tens of thousands of tickler SNPs (no prurient inuendos need be inferred here!) proved to have statistically significant effects in individual pairings, and hundreds accounted for the Yins of the subjects Yangs in more than one of the pairings.

The authors provide a table of the genes nearest to each of the 20 SNPs that gave hits in 3 different FCM pairings. For example, who could doubt FLJ46156 Protein -- we knew someone would discover it sooner or later! Likewise Drosophila (fly) sal-like 1, variant 1. It's indeed disappointing that these authors found this first, before we could. But that's science. Following up these leads will of course be the next stage, and probably a costly one at that even if, sadly, it probably has to be done in a lab, and not by questionnaire, thought if it requires mouse experiments, it is curious how the mice's Y's are to be evaluated.

These things are important because depending on your FCT which, even tho' there's a questionnaire, we can do a $10,000 gene chip to find out, your clinical treatment may vary. That's because, as with other kinds of Asian medicine (and indeed, some nonstandard medicines in the west, too) the same treatment may help, or harm, depending on the swing of your Yin. What's good for your goose may not be good for your gander, so to speak.

Of course, we have to note that the samples were rather small for genomewide studies compared to the best standard in, say, Europe: 20 vs 500,000. But let's not get our Yangs out of joint over that minor part of the problem.

Disappointingly, the authors fail to put this in evolutionary context, not looking to see whether measurement error (of the size of their subjects Yins or Yangs -- again, no scurrilous giggling out there, please!) might have affected fitness over the past millennia, that is, Nature screening GYAs, GYNs, and all, until Dr Lee came on the scene to formulate the FCM. But if having a mis-sized Yin (or dystorted Yang) affected fitness, we can easily see that the result today is a Korea that's far from genetically homogeneous, despite the authors claim to that effect.

We're not making this up! This is a paper you may not be able to get from your library, but is Yin et al, Journal of Alternative and Complementary Medicine, 15(12), 2009, pp 1327-1333. We must assume, unfortunately, that despite the journal's name, even in Korea medicine is not complementary and you actually have to pay for it. Free care would certainly never do here, where our eyes are always on the Yen, so to speak, rather than the Yin or Yang. So this paper may be of no direct relevance to our health-care dilemma. In the US, complimentary medicine may be free ("You look fine! You look good!"), but no free treatment, no matter your GYA-score.

In the end, GWAS of GYA and GYN vs LYN and LYA, to detect the FCT of your FCM, will get your mind all twisted round. It will make you simply want....a GIN!

(We thank Francesc Calafell for bringing this most important paper to our attention, so we could share it with the world.)


Unknown said...

And I in turn thank Urko Martinez for having pointed it out in our lab

John R. Vokey said...

Too funny. It gave me gwas. I may be up all night. Really, you people should publish a book: Oh, yes, you did: I wish all would buy it.

Anne Buchanan said...

Thanks, John! :-)