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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    • "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.
    Reviews in the neurosciences 04/2015; DOI:10.1515/revneuro-2014-0083 · 3.33 Impact Factor
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    • "This suggests that MDD is less likely than other psychiatric disorders to be caused by de novo genetic mutations that lead to biological malfunction. Despite this apparently reduced rate of malfunction, the global prevalence of unipolar depressive disorder is estimated to be eight times greater than bipolar disorder, 14 times greater than schizophrenia, and 34 times greater than autism (as reviewed by Uher (2009)). Furthermore, depression (unlike schizophrenia, autism, bipolar disorder, anorexia nervosa, or substance abuse disorder) was the only mental illness to be associated with a small but significant net fitness benefit in a recent analysis of 2.3 million Swedish hospital records (Power et al., 2013). "
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    ABSTRACT: Major depressive disorder (MDD) presents with a variety of symptoms and responds to a wide range of treatment interventions. Diagnostic criteria collapse multiple syndromes with distinct etiologies into the same disorder. MDD is typically understood as a malfunction of neurotransmission or brain circuitry regulating mood, pleasure and reward, or executive function. However, research from an evolutionary perspective suggests that the “normal” functioning of adaptations may also generate symptoms meeting diagnostic criteria. Functioning adaptations may be an underappreciated etiological pathway to MDD. Many adaptive functions for depressive symptoms have been suggested: biasing cognition to avoid losses, conserving energy, disengaging from unobtainable goals, signaling submission, soliciting resources, and promoting analytical thinking. We review the potential role of these adaptive functions and how they can lead to specific clusters of depressive symptoms. Understanding MDD from such a perspective reduces the heterogeneity of cases and may help to select the best intervention for each patient. We discuss the implications of different adaptive and maladaptive etiological pathways for the use of antidepressants and various modes of psychotherapy. In particular, instances of MDD caused by functioning adaptations may benefit most from treatments that support the adaptive function, or that target the precipitating causal stressor. We conclude that an evolutionary approach to the study of MDD may be one of the more promising approaches to reduce its heterogeneity and to better match patients and treatment.
    Journal of Affective Disorders 09/2014; 172. DOI:10.1016/j.jad.2014.09.032 · 3.38 Impact Factor
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    • "Earlier studies particularly accentuated deficits associated with the 5-HTTLPR short variant by demonstrating for instance increased fear-potentiated startle responses (Brocke et al., 2006), exaggerated amygdala activity in response to fearful faces (Hariri et al., 2002; Munafò et al., 2008) as well as an increased risk for depression and anxiety disorders in interaction with environmental factors (Lesch et al., 1996; Kenna et al., 2012). More recent reports however, have suggested a conceptual change based on findings which indicate that the s allele actually increases sensitivity not only to negative but also to positive stimuli pointing to a more general role of the 5-HTTLPR short variant in influencing environmental sensitivity (Uher, 2009; Homberg and Lesch, 2011). Fox and colleagues, for instance, reported that a low vs. a high 5-HTT group developed stronger biases for positive and negative affective pictures (Fox et al., 2011). "
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    ABSTRACT: Individual genetic differences in the serotonin transporter-linked polymorphic region (5-HTTLPR) have been associated with variations in the sensitivity to social and emotional cues as well as altered amygdala reactivity to facial expressions of emotion. Amygdala activation has further been shown to trigger gaze changes toward diagnostically relevant facial features. The current study examined whether altered socio-emotional reactivity in variants of the 5-HTTLPR promoter polymorphism reflects individual differences in attending to diagnostic features of facial expressions. For this purpose, visual exploration of emotional facial expressions was compared between a low (n = 39) and a high (n = 40) 5-HTT expressing group of healthy human volunteers in an eye tracking paradigm. Emotional faces were presented while manipulating the initial fixation such that saccadic changes toward the eyes and toward the mouth could be identified. We found that the low vs. the high 5-HTT group demonstrated greater accuracy with regard to emotion classifications, particularly when faces were presented for a longer duration. No group differences in gaze orientation toward diagnostic facial features could be observed. However, participants in the low 5-HTT group exhibited more and faster fixation changes for certain emotions when faces were presented for a longer duration and overall face fixation times were reduced for this genotype group. These results suggest that the 5-HTT gene influences social perception by modulating the general vigilance to social cues rather than selectively affecting the pre-attentive detection of diagnostic facial features.
    Frontiers in Behavioral Neuroscience 07/2014; 8:255. DOI:10.3389/fnbeh.2014.00255 · 3.27 Impact Factor
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