This really proves that resequencing has merit but will this have more value in less studied genes identified by GWAS? For instance 9p21. Will resequncing be useful in pharmacogenomics where cytochrome P450s have been fairly well studied? This might be the case. CYP2D6 was one of the first pharmacognetic genes discovered and associated with debrisoquine metabolism. There are a large number of functional SNPs that describe the 2D6 drug metabolising phenotype, some are common, some rare. Pseudogenes and CNVs have also been shown to influence 2D6 drug response. Would these have been discovered in a GWAS (I suppose no is the answer as the chips only did SNPs). The customised Roche Amplichip covers most of the 2D6 variants and it needed the breadth of a microarray to cover them all. It also covers 2C19 but not well enough to be clinically useful. One of the new factor Xa inhibitors is a 2D6 drug so this may be a useful tool in cardiology.

Also will the effects of the rarer variants be greater in some complex conditions rather than others? e.g. the example of neuroticism, which is hereditary, but GWAS on approx 2,000 subjects failed to find a hit.

Lots of questions. 

Dr. Topol, I just had the 9p21 genetic test which revealed my increased chances of cardiovascular disease disorders. My siblings and I have familial hypercholesterolaemia, we are all in our 50's. Our Father & grandmother had strokes from high cholesterol in their 60's which was so devastating for them and for us. Family melanoma also related to the 9p21 gene runs in our family. 

Please keep up the good work in the heart health and genetic field which can help prevent all of us from potential and serious outcomes. Thank You, Terri Higgins