In the current New England Journal of Medicine, David Goldstein wrote:
If common variants are responsible for most genetic components of type 2 diabetes, height, and similar traits, then genetics will provide relatively little guidance about the biology of these conditions, because most genes are “height genes” or “type 2 diabetes genes.”
In response, a friend of mine emailed and asked:
“What I find difficult to accept is that [Goldstein] has ongoing [genome-wide association] studies, so does he not believe in his own work?”
My response: I can’t speak for David, but having just read his commentary, I think he would say that if you’re going to do GWAS, the disease itself should probably not be the phenotype under study, because we’ve done those studies and so far they’ve produced a failry shitty ROI, at least by conventional definitions of clinical relevance. You’ll have more luck studying endophenotypes, e.g., drug response, brain structure as measured by MRI, a decline in working in memory, etc.
In an accompanying commentary, Joel Hirschhorn wrote:
I believe that the skeptics’ arguments either misconstrue the primary goal of genomewide association studies or are contradicted by their findings. The main goal of these studies is not prediction of individual risk but rather discovery of biologic pathways underlying polygenic diseases and traits. It is already clear that the genes being identified expose relevant biology.
Hmm. Yes of course we’ve learned a lot of biology, but isn’t this moving the goal posts a little bit? In the grants we write, do we not extol the clinical relevance of our work and the enormous promise it holds for diagnostics, therapeutics and–gasp!–actual cures for the diseases that ravage our species? Or do we modestly say, “Each discovery of a biologically relevant locus is a potential first step in a translational journey?” If we acknowledge that 100 years elapsed between the elucidation of the chemical makeup of cholesterol and the development of statins, does that make it okay? Given that 45 years have passed since the recognition that human response to anticoagulant drugs is genetically mediated and we STILL can’t agree about whether pharmacogenetic testing is a good idea, do we just shrug and say, “It is what it is?”
As I’ve said here before by way of disclosure, David Goldstein is a friend and colleague. Even if I don’t always agree with him (and I think he’s wrong when he offers the usual broad indictment of the personal genomics companies), I admire his willingness to — as Richard Preston said of Craig Venter — fart in church.
In the end I’ve had about enough of this debate. It is as if we are arguing over the merits of the compact disc when we all know its days are numbered. Within two years, I imagine that most everyone doing molecular human genetics and genomics of any kind will be sequencing whole genomes.
Whether anyone will understand the data is another matter…