The present array techniques do not enable hypothesis-free means of identifying high-risk variants with one exception: that of structural genomic variation.5 The process for reaching the goal of systematic identification of rare high-risk variants is clear, both from candidate-gene studies and from emerging techniques of high-throughput sequencing, which will soon permit the routine and complete sequencing of the human genome.19 Existing but imperfect intermediate techniques toward that goal are transcriptome sequencing and exome sequencing.34 The latter uses array techniques to pull exonic DNA from genomic DNA, which is then sequenced to give full representation of the coding genome. All coding polymorphisms in a subject will therefore be identifiable. Candidate-gene studies have already suggested the power of this type of approach. For example, Cohen and colleagues35 sequenced several genes encoding cholesterol-metabolizing proteins in patients with low plasma levels of high-density lipoprotein (HDL) cholesterol and found that rare variants were more common in case subjects who had low levels of HDL cholesterol than in control subjects. This example, in which a limited number of candidate genes were sequenced in a large number
