Be afraid of fear, not personal genomics.

It's just the way it is now. This headline. This story.
(click to read/hear)

As Genetic Sequencing Spreads, 

Excitement, Worries Grow

It follows the recipe. (1) Start with a headline that demonstrates controversy. (2) Present a story about science-related news (which does not require controversy to be news). (3) End it ever-so briefly and vaguely with dissent, doubt, outcry or warning. 

This recipe applied to personal genomics is particularly bad.

If you read or hear that story you might be primed before you start to wonder, okay what's the worry? Glad this article will tell me, finally, what we should be concerned about concerning this brave new world of personal genomics.

But you'll be sorry when you reach the end and this is all you get:

But the idea of widespread sequencing is setting off alarm bells. How accurate are the results? How good are doctors at interpreting the results, which are often complicated and fuzzy? How well can they explain the subtleties to patients? The fear is that a lot of people could end up getting totally freaked out for no reason. And there are concerns about privacy. Scientists recently even sequenced a fetus in the womb, raising the possibility of everyone getting sequenced before or at birth — a prospect with a whole new set of questions and concerns. "I think there are lots of populationwide and individual dangers," said Mark Rothstein, a bioethicist at the University of Louisville. "We're basically not ready for a society in which very exquisite, detailed genomic information about every individual, potentially, is out there."

Why? Tell us? And I don't mean the "us" who have access to the academic journals. Or the "us" who have the patience to bushwhack through the jargon. I mean, here is your chance to share with the public who you're concerned about: Since you brought it up, tell us why we should worry.

It's unclear who deserves the complaints and the criticism for producing pieces like this, since much of the "telling us" that I'm begging for might be lying on the cutting room floor.

I'm clenched about this because right now about 20 students in my Human Varition (Anthropology 350) course at the University of Rhode Island are voluntarily participating in genotyping through 23andMe. And I'm using this curriculum for the second semester now. After last spring, where over 100 students in both Human Variation and also the introductory level Human Origins (Anthropology 201) did 23andMe, not one student got "totally freaked out." This along with much of my experience with genotyping and undergraduates indicates that, with education and with understanding, personal genomics does not induce fear. Not coincidentally, participating in personal genomics aides in education.

And the same fear that I'm trying to mitigate through education is the same fear that some journalists and ethicists seem to be perpetuating if not creating.

In my experience, if you're informed, you're likely to appreciate biological complexity rather than cling to genetic determinism. If you're informed, you understand the positive and negative consequences and aspects of personal genomics. If you're informed, you don't get lured into personal genomics for all the wrong reasons. You don't order an expensive 23andMe spit kit as if it's snake oil. You don't send your vial of saliva to California, along with 300 of your precious bucks, because you think it will help you to live a longer, healthier life, or because you think it will show you your future.  Spit kits are not crystal balls, are not medicine, are not cures. Plus, the results will also most certainly change! Not your genotypes, but how they're interpreted. That genomes must even be "interpreted" should be a flag shouldn't it?

Informed citizens and consumers don't buy into personal genomics thinking it's their one and only answer-- their key to "me"-- because "me" will be increasingly different the more we learn about genetics and the links between genotypes and phenotypes. "Me" is, for most, too stubborn and conservative, while at once too big and too free, to be dictated by genotypes and probabilistic phenotypes.

All that is guaranteed with a 23andMe spit kit is that you will see parts of yourself that you haven't seen before. There's not a whole lot on the planet that's cooler than that. For most of us who will never go to Mars, at least we've got this, at least we've got innerspace.

Even if you don't get an ounce of joy from the experience, when you're informed you don't fall uncritically for claims that spit kits are dangerous or venomous.

Considering the engaging educational opportunites provided by personal genomics, considering its power to inform, spit kits may just be much-needed anti-venom.

In my experience education diminishes fear about genetic determinism because it diminishes genetic determinism. That leads me to see fear of personal genomics as a symptom of ignorance. And that's something worth being afraid of.

**

Note: Ken, Anne and I have differing views on direct-to-consumer (DTC) personal genomics like 23andMe so please remember that I speak only for myself when I write. Also, I am not paid  or sponsored by 23andMe to endorse their product. I use their product, at the educational rate, to teach anthropology at the University of Rhode Island.

GWAS: really, should anyone be surprised?

There's a story today in the New York Times about papers just published in the New England Journal of Medicine (embargoed for 6 months, so we can't link to it here) questioning the value of GWAS--genomewide association studies. We're interested because we, but largely Ken, often in collaboration with Joe Terwilliger at Columbia, have been writing for many years--in many explicit ways and for what we think are the right reasons, for 20 years or more--about why most common diseases won't have simple single gene, or even few gene explanations.

"The genetic analysis of common disease is turning out to be a lot more complex than expected," the reporter writes. Further, "...the kind of genetic variation [GWAS detect] has turned out to explain surprisingly little of the genetic links to most diseases." Of course, it depends on who's expectations you're talking about, and who you're trying to surprise. It may be a surprise for a genetics true-believer, but not for those who have been paying attention to the nature of genomic causation and how it evolved to be as it is (the critical facts and ideas have been known, basically, since the first papers in modern human genetics more than 100 years ago).

GWAS are the latest darling of the genetics community. Meant to identify common genetic factors that influence disease risk, the method scans the entire genome of people with and without the disease to look for genetic variants associated with disease risk. Many papers have been published claiming great success with this approach, and proclaiming that finally we're about to crack disease genetics and the age of personalized medicine is here. But upon scrutiny these successes turn out not to explain very much risk at all--often as little as 1%, 3% (even if the relative risk is, say 1.3--a 30% increase, or in a few cases 3.0 or more--there will always be excpetions). And this is for reasons that have been entirely predictable, based on what is known about evolution and genes.

Briefly, genes with major detrimental effects by and large are weeded out quickly by natural selection, most traits, including disease, except for the frankly single-gene diseases (which can stay around because they're partly recessive), are the result of many interacting genes, and, particularly for diseases with a late age of onset, environmental effects. And, there are many genetic pathways to any trait, so that the assumption that everyone with a given disease gets there the same way has always been wrong. Each genome is unique, with different, and perhaps rare or very rare genes contributing to disease risk and these will be difficult or impossible to find with current methods. Risk alleles can vary between populations, too--different genes are likely to contribute to diabetes in, say, Finns than in the Navajo. Or even the French. Or even different members of the same family! Inconvenient truths.

Now, news stories and even journal articles rarely point out any of these caveats. Indeed, David Goldstein is cited in the Times story as saying that the answer is individual whole genome sequencing, another very expensive and still deterministic approach (that surely will now be contorted by the proponents of big Biobanks to show that this is just the thing they've had in mind all along!). Nobody backs away from big long-term money just to satisfy what the science actually tells us. Now maybe there is the story, in the public interest, that a journalist ought to take on.

So, the push will be for ever-more complete DNA sequences to play with, but this is not in the public interest in the sense that it will not have major public health impact. Even if it identifies new pathways, one of the major rationales given in the face of the awkward epidemiological facts, which is unlikely to be a major outcome in public health terms. We have many ways to identify pathways, and more are becoming available all the time. While whole sequences can identify unique rare haplotypes or polygenotypes that some affected people share, that is really little more than trying the same method on new data, like Cinderella's wicked step-sisters forcing their feet into the glass slipper.

If it's true as it seems to be, that most instances of a disease are due to individually rare polygenotypes, then the foot will not fit be any better than before. And it won't get around the relative vs absolute risk, nor the environmental, nor the restrospective/prospective epistemiological problem. These are serious issues, but we'll have to deal with them separately. And the rarer the genotype the harder to show how often it is found in controls, hence the harder to estimate its effect.

------------------------
A few reasons why no one should be surprised:

*Update* Here are a few of the papers that have made these points in various ways and contexts over the years. They have references to other authors who have recently made some of these points. The point (besides vanity) is that we are not opportunistically jumping on a new bandwagon, now that more people are (more openly) recognizing the situation. In fact, the underlying facts and reasons have been known for even a far longer time.

The basic facts and theory were laid out early in the 20th century by some of the leaders of genetics, including RA Fisher, TH Morgan, Sewall Wright, and others.

Kenneth Weiss, Genetic Variation and Human Disease, Cambridge University Press, 1993.

Joseph Terwilliger, Kenneth Weiss, Current Opinion in Biotechnology, 9(6), 578-594 (1998). Linkage disequilibrium mapping of complex disease: fantasy or reality?

Kenneth Weiss, Joseph Terwilliger, Nature Genetics 26, 151 - 157 (2000). How many diseases does it take to map a gene with SNPs?

Joseph Terwilliger, Kenneth Weiss, Annals of Medicine 35: 532-544 (2003). Confounding, ascertainment bias, and the quest for a genetic "Fountain of Youth".

Kenneth Weiss, Anne Buchanan, Genetics and the Logic of Evolution, Wiley, 2004.

Joseph Terwilliger, Tero Hiekkalinna, European Journal of Human Genetics, 14, 426–437 (2006). An utter refutation of the 'Fundamental Theorem of the HapMap'.

Anne Buchanan, Kenneth Weiss, Stephanie M Fullerton, International Journal of Epidemiology, 35(3):562-571 (2006). Dissecting complex disease: the quest for the Philosopher's Stone?

Kenneth Weiss, Genetics 179, 1741–1756 (2008). Tilting at Quixotic Trait Loci (QTL): An Evolutionary Perspective on Genetic Causation.

Anne Buchanan, Sam Sholtis, Joan Richtsmeier, Kenneth Weiss, BioEssays, What are genes for or where are traits from? What is the question? BioEssays 31:198-208 (2009).