The third, or phenotype-stratified discovery approach, also goes from phenotype to genotype. It utilizes a specific subtype as the phenotype of interest and attempts to discover genomic regions harboring subtype-specific variants. Such analyses typically examine the contrast between a given illness subtype and controls. They are especially suited for discovery of what we have called modifier-susceptibility, or subtype-specific, loci.41 These are defined as loci that affect susceptibility to a more-orless phenotypically specific form of illness. Such genes have been demonstrated in somatic diseases. For example, FGFR2 is a susceptibility gene for estrogen receptor (ER)positive, but not ER-negative breast cancer,49,50 which is associated with a significantly worse prognosis. In this approach, phenotypic subtypes can be determined a priori. However, in schizophrenia studies, they have often been derived using empirical subtyping approaches, such as latent class analysis, based on lifetime ratings. This may be in part due to the limitations of