This review in Nature Neuroscience is excellent. I have never seen the issue of gene-environment interactions laid out so eloquently. Unfortunately, it is behind a subscription wall, so those of you not affiliated with a University may have to just live with this excerpt:
The recent history of psychiatric research that has measured genetic differences at the DNA sequence level can be divided into three approaches, each with its own logic and assumptions. The first approach assumes direct linear relations between genes and behaviour (Fig. 1a). The goal of this approach has been to correlate psychiatric disorders with individual differences in DNA sequence. This has been attempted using both linkage analysis and association analysis, with regard to many psychiatric conditions such as depression, schizophrenia and addiction. Although a few genes have accumulated replicated evidence of association with disorder, replication failures are routine and overall progress has been slow. Because of inconsistent findings, many scientists have despaired of the search for a straightforward association between genotype and diagnosis, that is, for direct main effects.
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The second approach has sought to make more progress by replacing the disorder outcomes with intermediate phenotypes, called ‘endophenotypes’ (Fig. 1b). Endophenotypes are heritable neurophysiological, biochemical, endocrinological, neuroanatomical or neuropsychological constituents of disorders. Endophenotypes are assumed to have simpler genetic underpinnings than disorders themselves. Therefore, this research approach pursues the hypothesis that it will be easier to identify genes associated with endophenotypes than genes associated with their correlated disorders. Although this approach substitutes the psychiatric diagnosis with an intermediate brain measure, it still searches for direct main effects.
The third approach to psychiatric genetics, unlike the first two approaches, seeks to incorporate information about the environment (Fig. 1c). This gene-environment interaction approach differs fundamentally from the ‘main-effect approaches’, with regard to the assumptions about the causes of psychiatric disorders. Main-effect approaches assume that genes cause disorder, an assumption carried forward from early work that identified single-gene causes of rare Mendelian conditions. By contrast, the gene-environment interaction approach assumes that environmental pathogens cause disorder, and that genes influence susceptibility to pathogens. In contrast to main-effect studies, there is no necessary expectation of a direct gene-to-behaviour association in the absence of the environmental pathogen. The gene-environment interaction approach has grown out of two observations: first, that mental disorders have environmental causes; second, that people show heterogeneity in their response to those causes. (Citations have been removed.)
Considering that I study schizophrenia and in part the genetics of schizophrenia, I would point out that this new model of disease formation poses a lot of problems for us. It is very difficult sometimes to relate genes to diseases when there are so many other confounding factors. But as my boss likes to say, “The low lying fruit have been picked…”