A Developmental Plasticity Model for Phenotypic Variation in Major Psychiatric Disorders

A DEVELOPMENTAL PLASTICITY MODEL FOR PHENOTYPIC variation in major psychiatric DISORDERS CHARLES DAVID MELLON* and LINCOLN D. CLARKt Introduction The ancient debate over nature versus nurture has been an area of serious scientific study for over 100 years [1, p. 131]. How does nature (genetic endowment at conception) interact with nurture (external forces = environment) to produce the phenotype (observable function, structure, or behavior)? For historical reasons, the early focus of this question was on complex phenotypes like intellectual ability, but, in the modern era, it is centered on the clinically important question of the contribution of genetic and environmental factors to the etiology of major psychiatric illnesses (particularly schizophrenia, bipolar disorder, and degenerative disorders such as Alzheimer's dementia). The major tool of psychiatric geneticists to study the nature-nurture question has been the twin-study paradigm. Twin studies were first suggested by Francis Galton in 1875 as a way to isolate the genetic variable, thus allowing the environmental variables to be understood [2]. Twin studies are unique in that identical (monozygotic) twins are 100 percent genetically identical at the time of the first cell division. This, in theory, leads to two genetically identical individuals. The implication is that the genetic component is fixed, so that any variation in phenotype is the result of the environment. The use of twin studies helped the nature versus nurture question evolve from the original argument over whether nature or nurture was C.D.M. is supported by a fellowship from the National Alliance for Research on Schizophrenia and Depression. *Research Fellow, Howard Hughes Medical Institute and the Department of Psychiatry, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, Utah 84132. tProfessor, Departments of Psychiatry and Pharmacology, University of Utah School of Medicine.© 1990 by The University of Chicago. AU rights reserved. 0031-5982/91/3401-0702$01 .00 Perspectives in Biology and Medicine, 34, 1 · Autumn 1990 \ 35 more important, to a model where genetic and environmental factors combine to determine the phenotypic expression. In this model, genetic and environmental factors are additive, thus generating an increasing vulnerability until a theoretical threshold is crossed, resulting in the disease phenotype [3]. It is now generally recognized that the demarcation of the disease phenotype and normal phenotype is not sharply defined but is represented as a gray area of symptoms usually referred to as spectrum disorders. The genetic/environmental paradigm is used as a model for all complex genetic disorders and has been canonized to the point that Gottesman and Shields state that "a basic postulate of contemporary human genetics is that all of a person's characteristics are the result of interaction between his genotype and his environment" [4, p. 315]. Diseases that are due to a defective gene should exist in both members of a twin pair if one of the twins is affected. This is referred to as 100 percent concordance. However, for schizophrenia, a bipolar disorder, and other psychiatric genetic disorders, the concordance rates fall below this, varying from 50 to 80 percent [5]. According to the genetic/environmental paradigm, this decreased monozygotic concordance is "proof" that environmental factors play a role in the etiology of major psychiatric disorders. Gottesman and Shields state this point unequivocally in their monograph on twin studies in schizophrenia: "The fact that the concordance rate for schizophrenia is very far from 100 percent in many studies is probably the best single piece of evidence there is pointing to the general importance of environmental factors—as yet unknown " [4, p. 291]. The role of environmental factors (primarily life events) in the etiology of major psychiatric disorders is seen by many mental health care professionals as being so obvious that it needs no scientific justification, but, when pressed, it is decreased monozygotic concordance that is usually held out as proof. Given its wide-ranging implications, the observation of decreased monozygotic concordance in major psychiatric illnesses deserves closer inspection. Two questions are obvious. First, if major psychiatric disorders are genetic diseases, why is the concordance rate not 100 percent? The answer might be that the studies were flawed and that some dizygotic pairs were used, or that there was some other technical problem. This...