Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.     

Evolution of sexual size dimorphism in birds: test of hypotheses using blue tits in contrasted Mediterranean habitats

Many hypotheses, either sex‐related or environment‐related, have been proposed to explain sexual size dimorphism in birds. Two populations of blue tits provide an interesting case study for testing these hypotheses because they live in contrasting environments in continental France and in Corsica and exhibit different degree of sexual size dimorphism. Contrary to several predictions, the insular population is less dimorphic than the continental one but neither the sexual selection hypothesis nor the niche variation hypothesis explain the observed patterns. In the mainland population it is advantageous for both sexes to be large, and males are larger than females. In Corsica, however, reproductive success was greater for pairs in which the male was relatively small, i.e. pairs in which sexual size dimorphism is reduced. The most likely explanation is that interpopulation differences in sexual size dimorphism are determined not by sex‐related factors, but by differences in sex‐specific reproductive roles and responses to environmental factors. Because of environmental stress on the island as a result of food shortage and high parasite infestations, the share of parents in caring for young favours small size in males so that a reduced sexual size dimorphism is not the target of selection but a by‐product of mechanisms that operate at the level of individual sexes.     

Epigenetics and memory: causes,consequences and treatments for post‐traumatic stress disorder and addiction

Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress‐related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug‐seeking responses. This may, in part, account for the fact that individuals with post‐traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug‐seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress‐induced relapse.     

Sex differences in molecular and cellular substrates of stress

Women are twice as likely as men to suffer from stress-related psychiatric disorders, like unipolar depression and post-traumatic stress disorder. Although the underlying neural mechanisms are not well characterized, the pivotal role of stress in the onset and severity of these diseases has led to the idea that sex differences in stress responses account for this sex bias. Corticotropin-releasing factor (CRF) orchestrates stress responses by acting both as a neurohormone to initiate the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator in the brain. One target of CRF modulation is the locus coeruleus (LC)-norepinephrine system, which coordinates arousal components of the stress response. Hypersecretion of CRF and dysregulation of targets downstream from CRF, such as the HPA axis and LC-norepinephrine system, are characteristic features of many stress-related psychiatric diseases, suggesting a causal role for CRF and its targets in the development of these disorders. This review will describe sex differences in CRF and the LC-norepinephrine system that can increase stress sensitivity in females, making them vulnerable to stress-related disorders. Evidence for gonadal hormone regulation of hypothalamic CRF is discussed as an effect that can lead to increased HPA axis activity in females. Sex differences in the structure of LC neurons that create the potential for hyperarousal in response to emotional stimuli are described. Finally, sex differences at the molecular level of the CRF(1) receptor that make the LC-norepinephrine system more reactive in females are reviewed. The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed.     

Post-translational histone modifications and their interaction with sex influence normal brain development and elaboration of neuropsychiatric disorders

Sex differences in the risk for and expression of various brain disorders have been known for some time. Yet, the molecular underpinnings of these sex differences as well as how sex modifies normal brain development are still poorly understood. It has recently become known that epigenetic mechanisms play an essential role in establishing and maintaining sex differences in neurodevelopment and disease susceptibility. Epigenetic mechanisms such as post-translational modifications of histones (histone PTMs) integrate various hormonal and external environmental influences to affect genomic output, and this appears to occur in a sex-dependent manner. The present review aims to highlight current understanding of the role of histone PTMs in the sexual differentiation of the brain under normal conditions and how sex-specific modulation of histone PTMs may be involved in psychiatric conditions including autism spectrum disorder (ASD), schizophrenia, and major depressive disorder (MDD). The role of sex chromosome genes as sex-specific histone modifiers and their importance in sexually differentiating the brain will be discussed. Further, the contribution of sex-specific histone PTM marks in the placenta in programming the sexually dimorphic developmental course of the brain and susceptibility to diseases/disorders will be reviewed. Prenatal programming may have a long-lasting effect on the adult brain and behavior but due to the interaction of histone PTMs and its modifiers with fluctuating hormone levels and external influences over the lifespan, the process remains dynamic. Although a few studies indicate an association between sex and histone PTM-related mechanisms in ASD, schizophrenia, and MDD, more research is needed to fully appreciate the interactive effects of histone PTMs and sex in the development and manifestation of these disorders. Understanding the interactions between sex and histone PTMs will advance our understanding of psychiatric disorders and potentially guide development of future treatments tailored specifically to each sex.     

Etiology in psychiatry: embracing the reality of poly‐gene‐environmental causation of mental illness

Intriguing findings on genetic and environmental causation suggest a need to reframe the etiology of mental disorders. Molecular genetics shows that thousands of common and rare genetic variants contribute to mental illness. Epidemiological studies have identified dozens of environmental exposures that are associated with psychopathology. The effect of environment is likely conditional on genetic factors, resulting in gene‐environment interactions. The impact of environmental factors also depends on previous exposures, resulting in environment‐environment interactions. Most known genetic and environmental factors are shared across multiple mental disorders. Schizophrenia, bipolar disorder and major depressive disorder, in particular, are closely causally linked. Synthesis of findings from twin studies, molecular genetics and epidemiological research suggests that joint consideration of multiple genetic and environmental factors has much greater explanatory power than separate studies of genetic or environmental causation. Multi‐factorial gene‐environment interactions are likely to be a generic mechanism involved in the majority of cases of mental illness, which is only partially tapped by existing gene‐environment studies. Future research may cut across psychiatric disorders and address poly‐causation by considering multiple genetic and environmental measures across the life course with a specific focus on the first two decades of life. Integrative analyses of poly‐causation including gene‐environment and environment‐environment interactions can realize the potential for discovering causal types and mechanisms that are likely to generate new preventive and therapeutic tools.     

Ca2+‐Dependent Hyperpolarization Pathways in Sleep Homeostasis and Mental Disorders

Although we are beginning to understand the neuronal and biochemical nature of sleep regulation, questions remain about how sleep is homeostatically regulated. Beyond its importance in basic physiology, understanding sleep may also shed light on psychiatric and neurodevelopmental disorders. Recent genetic studies in mammals revealed several non‐secretory proteins that determine sleep duration. Interestingly, genes identified in these studies are closely related to psychiatric and neurodevelopmental disorders, suggesting that the sleep‐wake cycle shares some common mechanisms with these disorders. Here we review recent sleep studies, including reverse and forward genetic studies, from the perspectives of sleep duration and homeostasis. We then introduce a recent hypothesis for mammalian sleep in which the fast and slow Ca²⁺‐dependent hyperpolarization pathways are pivotal in generating the SWS firing pattern and regulating sleep homeostasis, respectively. Finally, we propose that these intracellular pathways are potential therapeutic targets for achieving depolarization/hyperpolarization (D/H) balance in psychiatric and neurodevelopmental disorders.     

Testing structural models of psychopathology at the genomic level

Genome‐wide association studies (GWAS) have revealed hundreds of genetic loci associated with the vulnerability to major psychiatric disorders, and post‐GWAS analyses have shown substantial genetic correlations among these disorders. This evidence supports the existence of a higher‐order structure of psychopathology at both the genetic and phenotypic levels. Despite recent efforts by collaborative consortia such as the Hierarchical Taxonomy of Psychopathology (HiTOP), this structure remains unclear. In this study, we tested multiple alternative structural models of psychopathology at the genomic level, using the genetic correlations among fourteen psychiatric disorders and related psychological traits estimated from GWAS summary statistics. The best‐fitting model included four correlated higher‐order factors – externalizing, internalizing, thought problems, and neurodevelopmental disorders – which showed distinct patterns of genetic correlations with external validity variables and accounted for substantial genetic variance in their constituent disorders. A bifactor model including a general factor of psychopathology as well as the four specific factors fit worse than the above model. Several model modifications were tested to explore the placement of some disorders – such as bipolar disorder, obsessive‐compulsive disorder, and eating disorders – within the broader psychopathology structure. The best‐fitting model indicated that eating disorders and obsessive‐compulsive disorder, on the one hand, and bipolar disorder and schizophrenia, on the other, load together on the same thought problems factor. These findings provide support for several of the HiTOP higher‐order dimensions and suggest a similar structure of psychopathology at the genomic and phenotypic levels.     

Polygenic risk for psychiatric disorders correlates with executive function in typical development

Executive functions are a diverse and critical suite of cognitive abilities that are often disrupted in individuals with psychiatric disorders. Despite their moderate to high heritability, little is known about the molecular genetic factors that contribute to variability in executive functions and how these factors may be related to those that predispose to psychiatric disorders. We examined the relationship between polygenic risk scores built from large genome‐wide association studies of psychiatric disorders and executive functioning in typically developing children. In our discovery sample (N = 417), consistent with previous reports on general cognitive abilities, polygenic risk for autism spectrum disorder was associated with better performance on the Dimensional Change Card Sort test from the NIH Cognition Toolbox, with the largest effect in the youngest children. Polygenic risk for major depressive disorder was associated with poorer performance on the Flanker test in the same sample. This second association replicated for performance on the Penn Conditional Exclusion Test in an independent cohort (N = 3681). Our results suggest that the molecular genetic factors contributing to variability in executive function during typical development are at least partially overlapping with those associated with psychiatric disorders, although larger studies and further replication are needed.     

Etude des troubles psychiatriques et des mécanismes de défense psychologiques dans une population d’hommes stériles consultant en Andrologie

Results

26.2% of this population presented psychiatric disorders according to DSM-IV with a significant over-representation of generalized anxiety disorder and somatization disorder. The comparison between azoospermic males and oligoazoospermic males demonstrate the absence of significant difference in terms of psychiatric morbidity rate and use of defense styles. This population used similar defense modalities to the general population and preferentially used defense mechanisms corresponding to the mature defense style, such as humor, repression and anticipation. Psychiatric illness was significantly correlated with preferential use of withdrawal, consumption, reaction formation and lack of humor. This study also confirmed that subjects who essentially using neurotic defense styles were more likely to develop psychiatric disorders.

Conclusion

No difference in psychological effects was observed according to the degree of sterility. On the other hand, the presence of an over-representation of psychiatric disorders in sterile males compared to a control group indicates that Consultation-Liaison psychiatrists and andrologists must try to understand the patient’s suffering beyond the need for artificial insemination. Patients should therefore be given an opportunity to express all of the feelings related to their personal and marital drama in the department in which they are treated, as part of specialized management. Our study confirms the difficulty of determining whether certain defense mechanisms constitute risk factors for psychiatric disorders or whether defense mechanisms are an epiphenomenon of a particular psychiatric disorder, which is why many authors using DSQ agree that additional prospective studies are necessary to investigate correlations between defense mechanisms and specific psychiatric disorders. It would be useful to investigate defensive modalities before the diagnosis of infertility and after birth of a child in a larger population. A better understanding of the defensive modalities used by this type of population, in a psychotherapeutic context, could help to prevent or at least predict the appearance of psychiatric disorders.     

A case‐control study of brain structure and behavioral characteristics in 47,XXX syndrome

Trisomy X, the presence of an extra X chromosome in females (47,XXX), is a relatively common but under‐recognized chromosomal disorder associated with characteristic cognitive and behavioral features of varying severity. The objective of this study was to determine whether there were neuroanatomical differences in girls with Trisomy X that could relate to cognitive and behavioral differences characteristic of the disorder during childhood and adolescence. MRI scans were obtained on 35 girls with Trisomy X (mean age 11.4, SD 5.5) and 70 age‐ and sex‐matched healthy controls. Cognitive and behavioral testing was also performed. Trisomy X girls underwent a semi‐structured psychiatric interview. Regional brain volumes and cortical thickness were compared between the two groups. Total brain volume was significantly decreased in subjects with Trisomy X, as were all regional volumes with the exception of parietal gray matter. Differences in cortical thickness had a mixed pattern. The subjects with Trisomy X had thicker cortex in bilateral medial prefrontal cortex and right medial temporal lobe, but decreased cortical thickness in both lateral temporal lobes. The most common psychiatric disorders present in this sample of Trisomy X girls included anxiety disorders (40%), attention‐deficit disorder (17%) and depressive disorders (11%). The most strongly affected brain regions are consistent with phenotypic characteristics such as language delay, poor executive function and heightened anxiety previously described in population‐based studies of Trisomy X and also found in our sample.     

Post‐traumatic stress disorder: a state‐of‐the‐art review of evidence and challenges

Post‐traumatic stress disorder (PTSD) is arguably the most common psychiatric disorder to arise after exposure to a traumatic event. Since its formal introduction in the DSM‐III in 1980, knowledge has grown significantly regarding its causes, maintaining mechanisms and treatments. Despite this increased understanding, however, the actual definition of the disorder remains controversial. The DSM‐5 and ICD‐11 define the disorder differently, reflecting disagreements in the field about whether the construct of PTSD should encompass a broad array of psychological manifestations that arise after trauma or should be focused more specifically on trauma memory phenomena. This controversy over clarifying the phenotype of PTSD has limited the capacity to identify biomarkers and specific mechanisms of traumatic stress. This review provides an up‐to‐date outline of the current definitions of PTSD, its known prevalence and risk factors, the main models to explain the disorder, and evidence‐supported treatments. A major conclusion is that, although trauma‐focused cognitive behavior therapy is the best‐validated treatment for PTSD, it has stagnated over recent decades, and only two‐thirds of PTSD patients respond adequately to this intervention. Moreover, most people with PTSD do not access evidence‐based treatment, and this situation is much worse in low‐ and middle‐income countries. Identifying processes that can overcome these major barriers to better management of people with PTSD remains an outstanding challenge.     

Relevance of stress and female sex hormones for emotion and cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders.     

Combining redox-proteomics and epigenomics to explain the involvement of oxidative stress in psychiatric disorders

Psychiatric disorders affect approximately 10% of adults in North-America. The complex nature of these illnesses makes the search for their pathophysiology a challenge. However, studies have consistently shown that mitochondrial dysfunction and oxidative stress are common features across major psychiatric disorders, including bipolar disorder and schizophrenia. Nevertheless, little is known about specific targets of oxidation in the brain. The search for redox sensors (protein targets for oxidation) will offer information about which pathways are regulated by oxidation in psychiatric disorders. Additionally, DNA is also a target for oxidative damage and recently, studies have suggested that oxidation of cytosine and guanosine can serve as an epigenetic modulator by decreasing or preventing further DNA methylation. Therefore, this review aims to discuss how we can use redox-proteomics and epigenomics to help explain the role of oxidative damage in major psychiatric disorders, which may ultimately lead to the identification of targets for development of new medications.