Psychiatric genetics and the structure of psychopathology

For over a century, psychiatric disorders have been defined by expert opinion and clinical observation. The modern DSM has relied on a consensus of experts to define categorical syndromes based on clusters of symptoms and signs, and, to some extent, external validators, such as longitudinal course and response to treatment. In the absence of an established etiology, psychiatry has struggled to validate these descriptive syndromes, and to define the boundaries between disorders and between normal and pathologic variation. Recent advances in genomic research, coupled with large-scale collaborative efforts like the Psychiatric Genomics Consortium, have identified hundreds of common and rare genetic variations that contribute to a range of neuropsychiatric disorders. At the same time, they have begun to address deeper questions about the structure and classification of mental disorders: To what extent do genetic findings support or challenge our clinical nosology? Are there genetic boundaries between psychiatric and neurologic illness? Do the data support a boundary between disorder and normal variation? Is it possible to envision a nosology based on genetically informed disease mechanisms? This review provides an overview of conceptual issues and genetic findings that bear on the relationships among and boundaries between psychiatric disorders and other conditions. We highlight implications for the evolving classification of psychopathology and the challenges for clinical translation

Cross-cultural comparison of genetic and cultural transmission of smoking initiation using an extended twin kinship model

Background: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent–offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. Methods: We examined the role of genetic and environmental factors in individual differences for smoking initiation (SI) using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission, while also estimating the regression of the prevalence of SI on age. A dichotomous lifetime ‘ever’ smoking measure was obtained from twins and relatives in the ‘Virginia 30,000’ sample and the ‘Australian 25,000’. Results: Results demonstrate that both genetic and environmental factors play a significant role in the liability to SI. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission, and resulting genotype-environment covariance. Age regression of the prevalence of SI was significant. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent–offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (1) age × gene interaction, and (2) social homogamy. Neither of the mechanism provided a significantly better explanation of the data. Conclusions: This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on liability to SI

Highly neurotic never-depressed students have negative biases in information processing

BACKGROUND: Cognitive theories associate depression with negative biases in information processing. Although negatively biased cognitions are well documented in depressed patients and to some extent in recovered patients, it remains unclear whether these abnormalities are present before the first depressive episode. METHOD: High neuroticism (N) is a well-recognized risk factor for depression. The current study therefore compared different aspects of emotional processing in 33 high-N never-depressed and 32 low-N matched volunteers. Awakening salivary cortisol, which is often elevated in severely depressed patients, was measured to explore the neurobiological substrate of neuroticism. RESULTS: High-N volunteers showed increased processing of negative and/or decreased processing of positive information in emotional categorization and memory, facial expression recognition and emotion-potentiated startle (EPS), in the absence of global memory or executive deficits. By contrast, there was no evidence for effects of neuroticism on attentional bias (as measured with the dot-probe task), over-general autobiographical memory, or awakening cortisol levels. CONCLUSIONS: These results suggest that certain negative processing biases precede depression rather than arising as a result of depressive experience per se and as such could in part mediate the vulnerability of high-N subjects to depression. Longitudinal studies are required to confirm that such cognitive vulnerabilities predict subsequent depression in individual subjects

Clinical characteristics of familial generalized anxiety disorder

The authors seek to determine whether the clinical characteristics of generalized anxiety disorder (GAD) differ in individuals with a high vs. low familial vulnerability to illness. We identified 486 personally interviewed female twins from a population‐based register who had both an interviewed co‐twin and a lifetime history of GAD using modified DSM‐III‐R criteria which required a one‐month minimum duration of illness. We attempted to predict risk for GAD in the co‐twin from the clinical features of the GAD in the proband twin using the Cox proportional hazard model, controlling for year of birth and zygosity. Only two variables uniquely predicted an increased risk for GAD in the co‐twin: number of GAD symptoms endorsed and comorbidity with bulimia. Variables that did not uniquely predict risk of illness in the co‐twin included age at onset, duration of the longest episode and number of episodes. The familial vulnerability to GAD can be meaningfully indexed by clinical features of the syndrome. These results suggest that if the syndrome of GAD is to be narrowed, it would, from a familial perspective, be more valid to increase the minimum number of required symptoms rather than to increase the minimum duration of illness. Anxiety 1:186–191 (1994/1995). © 1995 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101797/1/3070010407_ftp.pd

Patterns of co-morbidity with anxiety disorders in Chinese women with recurrent major depression

BACKGROUND: Studies conducted in Europe and the USA have shown that co-morbidity between major depressive disorder (MDD) and anxiety disorders is associated with various MDD-related features, including clinical symptoms, degree of familial aggregation and socio-economic status. However, few studies have investigated whether these patterns of association vary across different co-morbid anxiety disorders. Here, using a large cohort of Chinese women with recurrent MDD, we examine the prevalence and associated clinical features of co-morbid anxiety disorders. METHOD: A total of 1970 female Chinese MDD patients with or without seven co-morbid anxiety disorders [including generalized anxiety disorder (GAD), panic disorder, and five phobia subtypes] were ascertained in the CONVERGE study. Generalized linear models were used to model association between co-morbid anxiety disorders and various MDD features. RESULTS: The lifetime prevalence rate for any type of co-morbid anxiety disorder is 60.2%. Panic and social phobia significantly predict an increased family history of MDD. GAD and animal phobia predict an earlier onset of MDD and a higher number of MDD episodes, respectively. Panic and GAD predict a higher number of DSM-IV diagnostic criteria. GAD and blood-injury phobia are both significantly associated with suicidal attempt with opposite effects. All seven co-morbid anxiety disorders predict higher neuroticism. CONCLUSIONS: Patterns of co-morbidity between MDD and anxiety are consistent with findings from the US and European studies; the seven co-morbid anxiety disorders are heterogeneous when tested for association with various MDD features

What is a mental disorder? An exemplar-focused approach

The question of ‘what is a mental disorder?’ is central to the philosophy of psychiatry, and has crucial practical implications for psychiatric nosology. Rather than approaching the problem in terms of abstractions, we review a series of exemplars – real-world examples of problematic cases that emerged during work on and immediately after DSM-5, with the aim of developing practical guidelines for addressing future proposals. We consider cases where (1) there is harm but no clear dysfunction, (2) there is dysfunction but no clear harm, and (3) there is possible dysfunction and/or harm, but this is controversial for various reasons. We found no specific criteria to determine whether future proposals for new entities should be accepted or rejected; any such proposal will need to be assessed on its particular merits, using practical judgment. Nevertheless, several suggestions for the field emerged. First, while harm is useful for defining mental disorder, some proposed entities may require careful consideration of individual v. societal harm, as well as of societal accommodation. Second, while dysfunction is useful for defining mental disorder, the field would benefit from more sharply defined indicators of dysfunction. Third, it would be useful to incorporate evidence of diagnostic validity and clinical utility into the definition of mental disorder, and to further clarify the type and extent of data needed to support such judgments

Major depression as a complex dynamic system

In this paper, we characterize major depression (MD) as a complex dynamical system in which symptoms (e.g., insomnia and fatigue) are directly connected to one another in a network structure. We hypothesize that individuals can be characterized by their own network with unique architecture and resulting dynamics. With respect to architecture, we show that individuals vulnerable to developing MD are those with strong connections between symptoms: e.g., only one night of poor sleep suffices to make a particular person feel tired. Such vulnerable networks, when pushed by forces external to the system such as stress, are more likely to end up in a depressed state; whereas networks with weaker connections tend to remain in or return to a healthy state. We show this with a simulation in which we model the probability of a symptom becoming active as a logistic function of the activity of its neighboring symptoms. Additionally, we show that this model potentially explains some well-known empirical phenomena such as spontaneous recovery as well as accommodates existing theories about the various subtypes of MD. To our knowledge, we offer the first intra-individual, symptom-based, process model with the potential to explain the pathogenesis and maintenance of major depression.Comment: 8 figure

A genetic analysis of coffee consumption in a sample of Dutch twins

Caffeine is by far the most commonly used psycho-active substance. Caffeine is consumed regularly as an ingredient of coffee. Coffee consumption and coffee preference was explored in a sample of 4,495 twins (including 1,231 pairs) registered with the Netherlands Twin Registry. Twin resemblance was assessed by tetrachoric correlations and the influence of both genetic and environmental factors was explored with model fitting analysis in MX. Results showed moderate genetic influences (39%) on coffee consumption. The remaining variance was explained by shared environmental factors (21%) and unique environmental factors (40%). The variance in coffee preference (defined as the proportion of coffee consumption relative to the consumption of coffee and tea in total) was explained by genetic factors (62%) and unique environmental factors (38%)

The diagnosis of mental disorders: the problem of reification

A pressing need for interrater reliability in the diagnosis of mental disorders emerged during the mid-twentieth century, prompted in part by the development of diverse new treatments. The Diagnostic and Statistical Manual of Mental Disorders (DSM), third edition answered this need by introducing operationalized diagnostic criteria that were field-tested for interrater reliability. Unfortunately, the focus on reliability came at a time when the scientific understanding of mental disorders was embryonic and could not yield valid disease definitions. Based on accreting problems with the current DSM-fourth edition (DSM-IV) classification, it is apparent that validity will not be achieved simply by refining criteria for existing disorders or by the addition of new disorders. Yet DSM-IV diagnostic criteria dominate thinking about mental disorders in clinical practice, research, treatment development, and law. As a result, the modernDSMsystem, intended to create a shared language, also creates epistemic blinders that impede progress toward valid diagnoses. Insights that are beginning to emerge from psychology, neuroscience, and genetics suggest possible strategies for moving forward

Eating disorders: from twin studies to candidate genes and beyond

Substantial effort has been put into the exploration of the biological background of eating disorders, through family, twin and molecular genetic studies. Family studies have shown that anorexia (AN) and bulimia nervosa (BN) are strongly familial, and that familial etiologic factors appear to be shared by both disorders. Twin studies often focus on broader phenotypes or subthreshold eating disorders. These studies consistently yielded moderate to substantial heritabilities. In addition, there has been a proliferation of molecular genetic studies that focused on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) AN and BN. Seven linkage regions have been identified in genome-wide screens. Many genetic association studies have been performed, but no consistent association between a candidate gene and AN or BN has been reported. Larger genetic association studies and collaborations are needed to examine the involvement of several candidate genes and biological pathways in eating disorders. In addition, twin studies should be designed to assist the molecular work by further exploring genetic determinants of endophenotypes, evaluating the magnitude of contribution to liability of measured genotypes as well as environmental risk factors related to eating disorders. In this manner twin and molecular studies can move the field forward in a mutually informative way