Uher, R. The role of genetic variation in the causation of mental illness: an evolution-informed framework. Mol. Psychiatry 14, 1072-1082

MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London, SE5 8AF, UK.
Molecular Psychiatry (Impact Factor: 14.5). 09/2009; 14(12):1072-82. DOI: 10.1038/mp.2009.85
Source: PubMed


The apparently large genetic contribution to the aetiology of mental illness presents a formidable puzzle. Unlike common physical disorders, mental illness usually has an onset early in the reproductive age and is associated with substantial reproductive disadvantage. Therefore, genetic variants associated with vulnerability to mental illness should be under strong negative selection pressure and be eliminated from the genetic pool through natural selection. Still, mental disorders are common and twin studies indicate a strong genetic contribution to their aetiology. Several theories have been advanced to explain the paradox of high heritability and reproductive disadvantage associated with the same common phenotype, but none provides a satisfactory explanation for all types of mental illness. At the same time, identification of the molecular substrate underlying the large genetic contribution to the aetiology of mental illness is proving more difficult than expected. The quest for genetic variants associated with vulnerability to mental illness is predicated upon the common disease/common variant (CDCV) hypothesis. On the basis of a summary of evidence, it is concluded that the CDCV hypothesis is untenable for most types of mental illness. An alternative evolution-informed framework is proposed, which suggests that gene-environment interactions and rare genetic variants constitute most of the genetic contribution to mental illness. Common mental illness with mild reproductive disadvantage is likely to have a large contribution from interactions between common genetic variants and environmental exposures. Severe mental illness that confers strong reproductive disadvantage is likely to have a large and pleiotropic contribution from rare variants of recent origin. This framework points to a need for a paradigm change in genetic research to enable major progress in elucidating the aetiology of mental illness.

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    • "One conclusion given the surprisingly high frequencies of many genetic variants associated with increased risk for maladaptive development under adverse environmental conditions is that such putative genetic risk variants are maintained in the population because they are also associated with reproductive advantages, most probably in response to different contextual conditions (Uher, 2009). In other words, the liability of a genetic variant associated with increased vulnerability under some conditions may be balanced by advantages associated with the same variant in alternative conditions. "
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    ABSTRACT: A large number of gene-environment interaction studies provide evidence that some people are more likely to be negatively affected by adverse experiences as a function of specific genetic variants. However, such "risk" variants are surprisingly frequent in the population. Evolutionary analysis suggests that genetic variants associated with increased risk for maladaptive development under adverse environmental conditions are maintained in the population because they are also associated with advantages in response to different contextual conditions. These advantages may include 1) co-existing genetic resilience pertaining to other adverse influences, 2) general genetic susceptibility to both low and high environmental quality, and 3) co-existing propensity to benefit disproportionately from positive and supportive exposures as reflected in the recent framework of Vantage Sensitivity. After introducing the basic properties of Vantage Sensitivity, and highlighting conceptual similarities and differences with Diathesis-Stress and Differential Susceptibility patterns of gene-environment interaction, selected and recent empirical evidence for the notion of Vantage Sensitivity as a function of genetic differences is reviewed. The unique contribution that the new perspective of Vantage Sensitivity may make to our understanding of social inequality will be discussed after suggesting neurocognitive and molecular mechanisms hypothesised to underlie the propensity to benefit disproportionately from benevolent experiences. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
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    • "In contrast, the s-allele might be indeed beneficial in " moderate " adverse environments with less social support and CA. Thus, our results support the assumption that the s-allele has not been sorted out by natural selection, because it might have positive behavioral effects in certain environments [Uher, 2009; Homberg and Lesch, 2011]. Bringing together all of the aforementioned findings, it seems possible that the examined interplay represents a " dynamic model " which depends on time, type and frequency of trauma as well as the accompanied quality of social support. "
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    ABSTRACT: Gene x environment interactions have mainly been investigated in models of psychopathology. However, the putative interplay between genes and beneficial environmental conditions on positive outcomes has rarely been addressed. We therefore examined the interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and social support on the sense of coherence (SOC), resilience, and depressive symptoms. Furthermore, we scrutinized our examinations by differentiating between individuals with and without childhood abuse. The sample included 1,811 participants from the general population (Study of Health in Pomerania, Germany). The triallelic genotype of 5-HTTLPR was determined and longitudinal data of social support were used. Among individuals with high social support no significant differences between 5-HTTLPR genotypes regarding all outcome variables were found. However, among those with low social support, carriers of at least one short allele reported significantly increased levels of SOC and resilience, as well as less depressive symptoms than carriers of the l/l genotype. This result was not modified by differentiating between those with childhood abuse and those without. In less supportive social environments the impact of distinct genotypes on behavioral outcomes might be more relevant than in supportive environments where social compensation might take place. Our findings indicate that both alleles of 5-HTTLPR contribute to the adaptability to different environmental conditions. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
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    • "Clinical studies highlight the fact that even severe stress exposure exacerbates/precipitates psychopathology in a relatively limited subset of individuals (Shalev et al., 1998). Preclinical studies in both rodent and non-human primate models recapitulate the individual variation in stress responses, with genetic background (Uher, 2009; Chaudhury et al., 2014; O'Leary et al., 2014) and life history, in particular early-life experience (Cirulli et al., 2009), serving as the backdrop that can strongly alter or modify the nature of outcomes evoked by stressors. Further, it is also necessary to draw attention to the fact that the same stressor can elicit opposing effects on structural versus synaptic changes, and different forms of anxiety and cognitive behaviors, thus indicative of differential vulnerability of these readouts to the same stressors. "
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    ABSTRACT: Exposure to stressors elicits a spectrum of responses that span from potentially adaptive to maladaptive consequences at the structural, cellular and physiological level. These responses are particularly pronounced in the hippocampus where they also appear to influence hippocampal-dependent cognitive function and emotionality. The factors that influence the nature of stress-evoked consequences include the chronicity, severity, predictability and controllability of the stressors. In addition to adult-onset stress, early life stress also elicits a wide range of structural and functional responses, which often exhibit life-long persistence. However, the outcome of early stress exposure is often contingent on the environment experienced in adulthood, and could either aid in stress coping or could serve to enhance susceptibility to the negative consequences of adult stress. This review comprehensively examines the consequences of adult and early life stressors on the hippocampus, with a focus on their effects on neurogenesis, neuronal survival, structural and synaptic plasticity and hippocampal-dependent behaviors. Further, we discuss potential factors that may tip stress-evoked consequences from being potentially adaptive to largely maladaptive.
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