The search for genenotype/phenotype associations and the phenome scan

All the approaches to the search for genotype/phenotype associations have their share of problems. Comparing the genome scan and candidate gene approaches, the former makes fewer assumptions at the genetic level or about mechanism but has greater statistical difficulties while the latter partially solves the statistical problem but makes more assumptions at both genetic and mechanistic levels. Among current difficulties is a lack of information about the nature of gene variant/phenotype associations: the frequency with which different classes of gene or sequence are involved; the type of genetic variation most commonly involved; the appropriate genetic models to apply to analysis. The overarching problem is that of multiple testing, one solution to which is to integrate genetic information to create a smaller number of compound variables. At the other end of the scale, decisions about the level of complexity at which to pitch the identification of phenotypes also affect the multiple testing problem: whether to pitch them at the level of disease outcomes, or at any of the multiple levels of intermediate phenotypes or traits. The third issue is how best to deal with gene/gene or gene/environment interactions, or whether to ignore them. Only as more genotype/phenotype associations emerge, by whatever means, will the numbers of results allow these questions to be answered. We describe here a new approach to genotype/phenotype association studies, the phenome scan, in which dense phenotypic information in human cohorts is scanned for associations with individual genetic variants. We believe that this approach can generate data that will be useful in answering generic questions about genotype/phenotype associations as well as in discovering novel ones.