Psychiatric Genetics: A Methodologic Critique

Virginia Institute for Psychiatry and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 02/2005; 162(1):3-11. DOI: 10.1176/appi.ajp.162.1.3
Source: PubMed


Psychiatric genetics, which is growing in size and influence within psychiatry, employs four major research paradigms: 1) basic genetic epidemiology, 2) advanced genetic epidemiology, 3) gene finding methods, and 4) molecular genetics. Paradigms 1 and 2 study aggregate genetic risk factors inferred from patterns of resemblance in relatives. Paradigms 3 and 4 study individual susceptibility genes localized on the human genome. Paradigms 1, 2, and 3 are statistical in nature, while paradigm 4 is biological. Genetic risk factors reflect the statistical signals from susceptibility genes. Whether it will be possible to identify all the susceptibility genes that underlie genetic risk factors is uncertain. Furthermore, given current research methods, the inability to detect susceptibility genes cannot disconfirm evidence for genetic risk factors. While paradigms 3 and 4 can provide great explanatory power by tracing etiologic pathways back to basic biological mechanisms, genetic epidemiology can also provide important etiologic insights, albeit of a less basic nature. While paradigms 3 and 4 may eventually replace paradigms 1 and 2, this shift is unlikely to occur quickly. Therefore, the field of psychiatric genetics would do best to integrate these four paradigms, stressing their relative strengths and limitations. This integration can be best done within an overall framework of explanatory pluralism that values a range of reductive explanations across varying levels of biological and psychological complexity.

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    • "Another often-heard phrase is " the path from genotype to phenotype, " and related metaphors such as the " genetic basis " for X (Hasler et al. 2006; Kendler 2005; MacQueen, Hajek, and Alda 2005). These expressions imply that genes are an organism's starting point, the prime mover, from which causality in ontogeny emanates outwards in space and onwards in time. "
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    ABSTRACT: Personalized medicine is the latest promise of a gene-centered biomedicine to provide treatments custom-tailored to the specific needs of patients. Although surrounded by much hype, personalized medicine at present lacks the empirical and theoretical foundations necessary to render it a realistic long-term perspective. In particular, the role of genetic data and the relationship between causal understanding, prediction, prevention, and treatment of a disease need clarifying. This article critically examines the concept of information in genetics and its relation to modern-day genetic determinism, using pharmacogenetics, personalized medicine's core discipline, as a test case. The article concludes that: (1) genetic knowledge does not constitute a privileged basis for personalized medicine because there is an a priori complete causal parity of genetic and nongenetic resources of development; and (2) prediction, prevention, and treatment all depend on a causal-mechanistic understanding that will follow only from integrating data across the whole gamut of developmental factors-genetic and non-genetic. In a future successful personalized medicine, genes will have no special status, either as determinants of phenotype, markers of disease or as targets of treatment.
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    • "Second, our findings of latent G × E also have key implications for molecular genetic research (Kendler, 2005). The suppression of genetic influences by prosocial peer affiliation implies that efforts to identify genetic main effects may be hampered by genetic suppression in particular environmental contexts. "
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    ABSTRACT: Background: Available research has suggested that affiliation with prosocial peers reduces child and adolescent antisocial behavior. However, the etiologic mechanisms driving this association remain unclear. The current study sought to evaluate whether this association takes the form of a gene-environment interaction (G × E) in which prosocial peer affiliation acts to reduce the consequences of genetic risk for non-aggressive antisocial behavior during childhood. Method: Our sample consisted of 500 twin pairs aged 6-10 years from the Michigan State University Twin Registry (MSUTR). Results: The results robustly support moderation by prosocial peer affiliation. Genetic influences on non-aggressive antisocial behavior were observed to be several times larger in those with lower levels of prosocial peer affiliation than in those with higher levels of prosocial peer affiliation. This pattern of results persisted even after controlling for gene-environment correlations and deviant peer affiliation, and when restricting our analyses to those twins who shared all or nearly all of their friends. Conclusions: Such findings not only suggest that prosocial peer affiliation moderates genetic influences on non-aggressive antisocial behaviors during childhood but also provide support for the theoretical notion that protective environmental experiences may exert their influence by promoting resilience to genetic risk.
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    • "First, it is important to recognize that the genetic influence on a phenotype (heritability) is not immutable ; it is dependent upon the environment. Indeed, it is most accurate to characterize heritability of an illness in terms of a specific population at a particular point in time (Kendler, 2005). Because different environmental factors may be relevant for different psychiatric illnesses in particular populations, it is difficult to Heritability : ' diseases ' versus behavioral disorders 37 address this limitation effectively. "
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