Whither the genotype‐phenotype relationship? An historical and methodological appraisal

More than a century ago, Wilhelm Johannsen proposed the terms “genotype” and “phenotype” to study heredity. Much of what we know about genetics and behavior has evolved since then, especially how causality from genotypes can be inferred from observational studies of phenotypes. Unfortunately, there are genotypes that produce complex clinical‐behavioral phenotypes—pleiotropy. In addition, there are often many genotypes that produce the same phenotype, adding a layer of complexity in establishing valid genotype‐phenotype relationships. Unlike the relative simplicity of some phenotypes, behavioral phenotypes, especially those characteristics considered aberrant, are multidimensional and often not easily defined operationally. An alternate approach which attempts to identify less evident manifestations below the level of the phenotype but along the pathway to the prospective genotype—endophenotypes—could prove useful in detecting genes that generate these markers. However, operational definitions of intermediate phenotypes vary, less overt neurobiological expressions for some disorders—autism—have not been found, and studies of endophenotypes associated with schizophrenia have been not