As someone who works on depression GWAS, this isn't the end of finding causal genes for depression, it's the beginning.
In the next few years we're going to see a waterfall of new rare variants linked to disease, all which have a much higher chance of causing functional change.
As WGS comes online for association studies it will both validate and more deeply explore the genetic nature of every disease. It is going to be mindblowing.
> As WGS comes online for association studies it will both validate and more deeply explore the genetic nature of every disease. It is going to be mindblowing.
But there is another layer of confusion, because WGS implies resequencing, and resequencing is only as good as your reference genome, and will distort results when the genome you're inferring is to far from the reference (reference bias).
The real mind bend will come when we have thousands or millions of whole genome de novo assemblies and we compare these to each other to do our GWAS. Only then are we going to have a hope of knowing what is actually causal in a genomic sense. Until then we remain in the land of association.
In nature, most adaptive variation appears to be large and structural. All the recent studies that have used whole genome assemblies to look at this have found the same thing. I would be surprised if this isn't the case for humans too. If it is, then much of current perspective on GWAS (both based on chips and WGS) will need to be rewritten.
GWAS is nothing more than correlations and by themselves aren't very remarkable. What is remarkable is when someone does a functional analysis on the variant they found in their GWAS and is able to describe the mechanism that it uses to affect the disease or phenotype. The way you do that isn't more sequencing, but with model systems that you can easily manipulate in the lab.
GWAS also doesn't compare to an arbitrary reference sequence. Some good numbers for a GWAS are >1000 cases and >2000 controls from the same population. You have to match populations, or else all your association study is going to find is the differences between east asians and europeans, for example. You need a lot of samples to get enough stats power to even see these rare variants.
In the next few years we're going to see a waterfall of new rare variants linked to disease, all which have a much higher chance of causing functional change.
As WGS comes online for association studies it will both validate and more deeply explore the genetic nature of every disease. It is going to be mindblowing.