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

Abstract

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 been very successful. Another approach, suggested by Sewall Wright, uses path analysis to identify causal variables that produce phenotypes. Innovative models of causality have been developed recently by genetic epidemiologists that incorporate Mendel's second law, and Mendelian randomization has been successful in identifying genotypes associated with some diseases, for example, diabetes and cancer. Regrettably, shortcomings regarding genetic markers associated with intermediate phenotypes have been found, although there are statistical procedures to remedy matters. As in any science, genetic researchers need to consider carefully the models of causality they choose.

Genetics and Epigenetics of Schizophrenia

“…Second is the problem of Psychotic Disorders -An Update genotype-phenotype relationship. After a century ago, when Wilhelm Johannsen proposed the terms "genotype" and "phenotype," our knowledge about the genetics, phenotype, and the concept of causality has evolved dramatically [18]. For example, genotype heterogeneity means that there are many genotypes that produce the same phenotype.…”

“…Another approach may be the path analysis to identify causal variables that produce phenotypes [21,22]. However, the chosen models of causality are very important [18]. Third is the genetic hypothesis being tested.…”

Deep Phenotyping in the -Omic Era: Methodological Issues Facing Neuropsychiatric Disorders

“…The genotype was "the sum total of all genes", and the phenotype evidenced by "direct inspection… or finer measures of assessment" of the organism under consideration. Embedded in Johannsen's conception of the genotype-phenotype relationship was a model of causality: the genotype of the parent transmitted to the offspring produced the latter's phenotype [9] .…”

Phenotypes, pleiotropy, and phylogeny

“…Also, of prote omes , gen omes , etc., a practice begun by Plate: Mendelom(e) curiously now absent from our vocabulary. The challenge remaining for those working with so‐called “endophenotypes” (Fisch, ; Lewis & John, , , within), that is, mostly functional phenotypes without any identifying physical developmental manifestations or correlates, consists of a phenotype analysis so discerning as to allow ordering of manifestations of the genetically caused or ‐predisposed condition as pleiotropic or non‐pleiotropic, (i.e., always together or randomly associated), primary or secondary (i.e., loss of cognitive functions in a tuberous sclerosis patient with uncontrolled seizures, or obesity in Prader–Labhart–Willi syndrome).…”