algorithm could be ‘positive’ for an associated non-causal SNP and ‘negative’ for a causal LD proxy. This could artificially inflate the estimate of prediction. The confirmation of pathogenesis may be more straightforward for highly penetrant mutations causing rare Mendelian disorders. Tools that predict the effect of amino acid substitutions, such as PolyPhen (10) and SIFT (9,39), have been shown to have predictive power for Mendelian disorders. PolyPhen predictions have been incorporated into SPOT and their influence on priority can be configured by the user. GWAS, however, are more directly aimed at common complex disease (40,41), and it is an enormous challenge to assemble a collection of causal variants for common complex disease that meets these rigorous criteria for validation, in particular the disambiguation of LD proxies, that is of sufficient size to assess predictive power. While projects such as GEN2PHEN (http://www.gen2phen.org) and the Human Variome Project (15) aim to solve this problem [see (42) for a general review], it would appear that currently the resource closest to meeting these validation criteria is the database maintained by the National Human Genome Research Institute containing published GWAS associations with P < 10−5 from the statistical test for association (http://www.genome.gov/gwastudies/) (38), although this
