In the first, an intermediate phenotype includes physiology relevant to understanding disease pathogenesis. Suppose that a psychiatric disease arises in part from a disordered neuronal circuit, whose anatomical location and components are unknown. If a phenotype can be found that specifically reflects activity in that circuit, the phenotype can be described as more coherent than the disease, reflecting a process that gives rise to disease. In the extreme case, the use of intermediate phenotypes could reduce pathogenesis to a molecular change, as was possible for sickle cell anemia, an inherited blood disorder. Sickle cell patients possess a mutation that replaces the hydrophilic amino acid glutamic acid with the hydrophobic amino acid valine at the sixth position of the beta chain of the haemoglobin molecule. Losing a polar amino acid enhances the molecular aggregation of haemoglobin, altering the shape of the red blood cell so that it loses plasticity, distorts, and occludes blood vessels with life-threatening consequences. Measurements of how a normal blood cell navigates the body’s circulation, which in turn depend on information about membrane mechanics and circulatory competence, are the equivalents of the intermediate phenotypes of brain structure, memory and intelligence assayed in a study of schizophrenia.
