WHY SCHIZOPHRENIA GENETICS NEEDS EPIGENETICS: A REVIEW

Schizophrenia (SZ) is a highly heritable disorder, with about 80% of the variance attributable to genetic factors. There is accumulating evidence that both common genetic variants with small effects and rare genetic lesions with large effects determine risk of SZ. As recently shown, thousands of common single nucleotide polymorphisms (SNPs), each with small effect, cumulatively could explain about 30% of the underlying genetic risk of SZ. On the other hand, rare and large copy number variants (CNVs) with high but incomplete penetrance, variable in different individual, could explain about additional 30% of SZ cases. Although these rare CNVs frequently develop de novo, it is not clear whether they affect risk independently or via interaction with a polygenic liability in the background. Finally, the role of environmental risk factors has been well established in SZ. Environmental factors are rarely sufficient to cause SZ independently, but act in parallel or in synergy with the underlying genetic liability. Epigenetic misregulation of the genome and direct CNS injury are probably the main mechanism to mediate prenatal environmental effects (e.g., viruses, ethanol, or nutritional deficiency) whereas postnatal risk factors (e.g., stress, urbanicity, cannabis use) may also affect risk via usebased potentiation of vulnerable CNS pathways implicated in SZ. In this review, we outline a general theoretical background of epigenetic mechanisms involved in GxE interactions, and then discuss epigenetic and neurodevelopmental features of SZ based on available information from genetics, epigenetics, epidemiology, neuroscience, and clinical research. We argue that epigenetic model of SZ provides a framework to integrate a variety of diverse empirical data into a powerful etiopathogenetic synthesis. The promising future of this model is the possibility to develop truly specific prevention and treatment strategies for SZ

Neuroscience of object relations in health and disorder: A proposal for an integrative model

Recent advances in the neuroscience of episodic memory provide a framework to integrate object relations theory, a psychoanalytic model of mind development, with potential neural mechanisms. Object relations are primordial cognitive-affective units of the mind derived from survival- and safety-level experiences with caretakers during phase-sensitive periods of infancy and toddlerhood. Because these are learning experiences, their neural substrate likely involves memory, here affect-enhanced episodic memory. Inaugural object relations are encoded by the hippocampus-amygdala synaptic plasticity, and systems-consolidated by medial prefrontal cortex (mPFC). Self- and object-mental representations, extracted from these early experiences, are at first dichotomized by contradictory affects evoked by frustrating and rewarding interactions ( partial object relations ). Such affective dichotomization appears to be genetically hardwired the amygdala. Intrinsic propensity of mPFC to form schematic frameworks for episodic memories may pilot non-conscious integration of dichotomized mental representations in neonates and infants. With the emergence of working memory in toddlers, an activated self- and object-representation of a particular valence can be juxtaposed with its memorized opposites creating a balanced cognitive-affective frame (conscious integration of object relations ). Specific events of object relations are forgotten but nevertheless profoundly influence the mental future of the individual, acting (i) as implicit schema-affect templates that regulate attentional priorities, relevance, and preferential assimilation of new information based on past experience, and (ii) as basic units of experience that are, under normal circumstances, integrated as attractors or focal points for interactive self-organization of functional brain networks that underlie the mind. A failure to achieve integrated object relations is predictive of poor adult emotional and social outcomes, including personality disorder. Cognitive, cellular-, and systems-neuroscience of episodic memory appear to support key postulates of object relations theory and help elucidate neural mechanisms of psychodynamic psychotherapy. Derived through the dual prism of psychoanalysis and neuroscience, the gained insights may offer new directions to enhance mental health and improve treatment of multiple forms of psychopathology

AN INTEGRATIVE MODEL AND DYNAMIC NOSOLOGY OF PERSONALITY DISORDER: PART 2: SYMPTOM-BASED PHARMACOTHERAPY

This paper presents an integrative model of personality and personality disorder which incorporates psychoanalytic concepts with modern neuroscience. In addition, a dynamic, personalized, and context - and time-sensitive diagnosis of personality disorder is introduced. The authors cogently argue that all clinical variants of personality disorder share the same common deficit: fragmented basic units of experience at the nonconscious core of the mind (aka “partial object relations”). The fragmentation propagates through mental faculties (thought, motivation, emotion), as they self-organize into subsystems of personality, e.g., one’s sense of self, identity, character, moral values, rendering them polarized into extreme and thus adaptively suboptimal. The syndrome of personality disorder arises as a nonconscious compensatory maneuver of the fragmented mind to organize itself through a defensive but unrealistic self-image (e.g., narcissistic, schizoid, antisocial, etc.), giving rise to a host of unique symptoms. Symptomatic pharmacotherapy of personality disorder is best organized around four empirically derived domains of symptoms, shared by all variants to a variable degree: i) mood and anxiety dysregulation; ii) impulsivity, aggression, and behavior dyscontrol; iii) emotional disinterest and detachment; and iv) cognitive distortions and brief reactive psychoses. Pharmacotherapy targeting the above domains is nonspecific, as medications affect multiple domains simultaneously. Modest empirical evidence and considerable clinical benefits continue to support the use of medications in the overall symptomatic treatment of personality disorder

AN INTEGRATIVE MODEL OF PERSONALITY DISORDER: PART 3: MECHANISM-BASED APPROACH TO THE PHARMACOTHERAPY OF PERSONALITY DISORDER: AN EMERGING CONCEPT

Temperament traits of Novelty Seeking, Harm Avoidance, Reward Dependence, and Persistence, are well defined in terms of their neural circuitry, neurochemical modulators, and patterns of associative learning. When heritably excessive, each of these traits may become a mechanistically fundamental biogenetic trait vulnerability for personality disorder. The other main risk factor for personality disorder is environmental, notably abuse, neglect, and psychological trauma. The emerging concept of mechanism-based pharmacotherapy aims to activate the brain’s homeostasis as the only available delivery system to re-calibrate complex neurophysiological participants in each of the temperament traits. In a positive feedback, a homeostasis-driven improvement of excessive temperament is expected to facilitate maturation of neocortical networks of cognition, most reliably in expert psychotherapy (Part I of this paper) and, ultimately, thereby improve top-down cortical control of subcortical affect reactivity. As an emerging concept informed by neuroscience and clinical research, mechanism based pharmacotherapy has the potential to be superior to traditional symptom-based treatments. Such mechanism-based approach illustrates what the pharmacological treatment of Research Domain Criteria (RDoC) might look like

The influence of COMT Val158Met genotype on the character dimension cooperativeness in healthy females

Objectives: Although the Val(158)Met catechol-O-methyltransferase (COMT) gene has been linked with the temperament dimension Novelty Seeking (NS), new insights in this polymorphism might point to a major role for character features as well. Given that individual life experiences may influence Val(158) and Met(158) allele carriers differently it has been suggested that the character trait cooperativeness could be implicated. Case report: A homogeneous group of eighty right-handed Caucasian healthy female university students were assessed with the TCI and genotyped for the COMT Val(158)Met polymorphism (rs4680). Gene determination showed that eighteen were Val(158) homozygotes, forty-four Val/Met(158) heterozygotes, and eighteen were Met(158) homozygotes. All were within the same age range and never documented to have suffered from any neuropsychiatric illness. Bonferroni corrected non-parametric analyses showed that only for the character scale cooperativeness Val(158) homozygotes displayed significant higher scores when compared to Met(158) homozygotes. No significant differences on cooperativeness scores were found between Val(158) and Val/Met(158) carriers or between Met(158) and Val/Met(158) carriers. No differences were observed for the COMT Val(158) Met polymorphism and the other temperament and character scales. Conclusions: Our findings support the assumption that the Val(158)Met single nucleotide polymorphism (SNP) influences character traits and not only temperament. Our results add to the notion that Val(158) homozygotes are considered to be helpful and empathic and it suggest that these cooperativeness character traits are related to the dopaminergic system

Ferromagnetic phase transitions of inhomogeneous systems modelled by square Ising models with diamond-type bond-decorations

The two-dimensional Ising model defined on square lattices with diamond-type bond-decorations is employed to study the nature of the ferromagnetic phase transitions of inhomogeneous systems. The model is studied analytically under the bond-renormalization scheme. For an $n$-level decorated lattice, the long-range ordering occurs at the critical temperature given by the fitting function as $(k_{B}T_{c}/J)_{n}=1.6410+(0.6281) \exp [ -(0.5857) n]$, and the local ordering inside $n$-level decorated bonds occurs at the temperature given by the fitting function as $(k_{B}T_{m}/J)_{n}=1.6410-(0.8063) \exp [ -(0.7144) n]$. The critical amplitude $A_{\sin g}^{(n)}$ of the logrithmic singularity in specific heat characterizes the width of the critical region, and it varies with the decoration level $n$ as $A_{\sin g}^{(n)}=(0.2473) \exp [ -(0.3018) n]$, obtained by fitting the numerical results. The cross over from a finite-decorated system to an infinite-decorated system is not a smooth continuation. For the case of infinite decorations, the critical specific heat becomes a cusp with the height $c^{(n)}=0.639852$. The results are compared with those obtained in the cell-decorated Ising model.Comment: 18 pages, 7 figure

Uncovering the complex genetics of human character

Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory