Nature and nurture interplay: schizophrenia

There is compelling evidence from family, twin and adoption studies of a substantial genetic contribution to schizophrenia. The mode of transmission is complicated and very rarely if ever involves a single gene. Rather schizophrenia results from multiple genes of small effect and their interplay with the environment. Perhaps because the overall size of the genetic effect is large, accounting for about 80 % of variance, definite environmental factors have been difficult to pin down. It has even been suggested that "the environment" consists entirely of epigenetic or stochastic phenomena that can never be detected by a standard epidemiological methods. Nevertheless, a variety of social stressors, including high expressed emotion in relatives and life events affect the course of illness and certain physical factors such as obstetric complications and cannabis smoking have been implicated in contributing to liability to the disorder. The recent discovery of several positional candidate genes that have been replicated as being associated with liability to schizophrenia holds considerable promise not just for a better understanding of the neurobiology but also for improved knowledge about risk prediction and gene-environment interplay.     

How and why genetic linkage has not solved the problem of psychosis: review and hypothesis

OBJECTIVE: The author examined the chromosomal linkage method as an approach to the genetic basis of schizophrenia and bipolar disorder. METHOD: Comparisons were conducted of recent meta-analyses of genome scans of schizophrenia and bipolar disorder and of the three largest (N>300) sibling pair studies of schizophrenia and schizoaffective disorder and a comparable study of bipolar illness. RESULTS: Recent meta-analyses have not identified consistent sites of linkage. The three largest studies of schizophrenia fail to agree on a single locus, no commonality with bipolar illness has been demonstrated, and there is no replicable support for any of the current candidate genes. DISCUSSION: An alternative to the concept that DNA sequence variation lies in "multiple genes of small effect" is the hypothesis that the variation is epigenetic but related to the genetic transition ("the speciation event") that separated Homo sapiens from a prior hominid species. This hypothesis draws attention to the chromosomal rearrangement (the Xq21.3/Yp translocation) that occurred some 6 million years ago in the hominid lineage and subsequent rearrangements, including a paracentric inversion, that have taken place within the translocated segment. Here it is argued that the most recent of these events is relevant to specifically human characteristics, including language. The gene pair protocadherin X and Y within this region is under new selective pressure and is in a novel (epigenetic) situation with respect to X inactivation. CONCLUSIONS: Epigenetic variation associated with chromosomal rearrangements that occurred in the hominid lineage and that relates to the evolution of language could account for predisposition to schizophrenia and schizoaffective and bipolar disorder and failure to detect such variation by standard linkage approaches.     

Genetic and other factors in schizophrenic, manic-depressive, and schizo-affective psychoses.

The major psychoses have been investigated for genetic and environmental etiological factors for over two centuries. Recent emphasis has been placed on a genetic (diathesis) environmental stress model. For schizophrenia, manic-depressive, and schizo-affective psychoses, research evidence from psycho-biological studies, family, pedigree, twin, and adoptee studies has provided sufficient data from diagnostic and follow-up studies and new psychopharmacological research that for these three major psychoses a strong necessary but not sufficient basis for genetic causation exists. This review attempts to summarize existing data into a hypothesis that suggests that two separate gene pools of polygenic nature relate to the development of schizophrenia and manic-depressive illness and that schizo-affective illness may result from genetic transmission from each of these separate gene pools. The hypothetical model for each psychosis proposes that polygenetic inheritance affects different central nervous system neuroanatomical sites in the human which are in homeostasis as to catecholamine neurotransmitter regulation of the psyche. With sufficient environmental stress, an "imbalance" occurs in the neural integrative systems which produces phenotypically the three separate psychotic behavioral syndromes of schizophrenia, manic-depressive psychosis, and schizo-affective psychosis.     

Epileptogenesis: Can the Science of Epigenetics Give Us Answers?

Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy development known as epileptogenesis. The purpose of this article is to discuss recent findings suggesting that the process of epileptogenesis may alter the epigenetic landscape, affecting the gene expression patterns observed in epilepsy. Future studies focused on a better characterization of these aberrant epigenetic mechanisms hold the promise of revealing novel treatment options for the prevention and even the reversal of epilepsy.The underlying cause of epilepsy in patients is still largely unknown, leaving 1 to 2% of the population without a cure and making the search for new treatments ever more urgent. Current treatment options for the epilepsies have been largely focused on and are effective at controlling seizure activity in most cases; however, cures for these disorders have been elusive. This is largely owing to the very complex progression of the disease state and the multiple inherited and acquired factors that can influence the onset and progression of epilepsy disorders. An emerging idea is that exploring epigenetic mechanisms, including covalent modifications of histones and DNA, may provide insight into how inherited or acquired alterations in the steady-state expression patterns of genes in the brain contribute to epileptogenesis.During the past decade the science of epigenetics has advanced our understanding of the complex relationship between genetic and environmental factors that orchestrate expression of genes under numerous physiologic conditions. Accordingly, aberrant epigenetic regulation of genes has been implicated in several CNS disorders, including stroke, Alzheimer disease, schizophrenia, and depression (1, 2). Epilepsy is no exception, in that abnormalities in the expression and regulation of epigenetic factors offer a provocative locus for the integration of common pathways that may reveal novel insights into the development of this disease.     

Epigenetic Age Acceleration Was Delayed in Schizophrenia

Schizophrenia is a serious neuropsychiatric disorder with abnormal age-related neurodevelopmental (or neurodegenerative) trajectories. Although an accelerated aging hypothesis of schizophrenia has been proposed, the quantitative study of the disruption of the physiological trajectory caused by schizophrenia is inconclusive. In this study, we employed 3 “epigenetic clock” methods to quantify the epigenetic age of a large sample size of whole blood (1069 samples from patients with schizophrenia vs 1264 samples from unaffected controls) and brain tissues (500 samples from patients with schizophrenia vs 711 samples from unaffected controls). We observed significant positive correlations between epigenetic age and chronological age in both blood and brain tissues from unaffected controls and patients with schizophrenia, as estimated by 3 methods. Furthermore, we observed that epigenetic age acceleration was significantly delayed in schizophrenia from the whole blood samples (aged 20–90 years) and brain frontal cortex tissues (aged 20–39 years). Intriguingly, the genes regulated by the epigenetic clock also contained schizophrenia-associated genes, displaying differential expression and methylation in patients with schizophrenia and involving in the regulation of cell activation and development. These findings were further supported by the dysregulated leukocyte composition in patients with schizophrenia. Our study presents quantitative evidence for a neurodevelopmental model of schizophrenia from the perspective of a skewed “epigenetic clock.” Moreover, landmark changes in an easily accessible biological sample, blood, reveal the value of these epigenetic clock genes as peripheral biomarkers for schizophrenia.     

Clinical genetics as clues to the "real" genetics of schizophrenia (a decade of modest gains while playing for time)

Although a decade has passed since the genetics of schizophrenia was examined for the Schizophrenia Bulletin, the epigenetic puzzle of schizophrenia has not yielded its secrets to any scientific break-through. In this article we review a sample of the highlights relevant to enlightened genetic thinking, i.e., a broad diathesis-stressor framework with multifactorial causation assumed and with provision for the epigenetic interaction of psychosocial as well as neurobiological factors. The clinical genetic epidemiologist needs to know the lifetime morbid risks generated by different definitions of schizophrenia, as well as the consequences for the familial risks generated by the various family, twin, and adoption strategies. Schizophrenia appears to occur through an interaction of a genetic susceptibility with some kind of environmental stress; the stress need not be an environment containing a person with a diagnosis in the schizophrenia spectrum; the genetic factors in schizophrenia have specificity as they do not increase the risk for major affective disorders or delusional disorder. Clearly, schizophrenia is clinically or phenotypically heterogeneous, but whether this variety is paralleled by etiological heterogeneity or to what extent is problematic. Once the existence of an important genetic predisposition to developing schizophrenia has been established, it becomes important to provide a theory (or theories) to account for its mode (modes) of transmission. Psychiatric geneticists have not yet solved the problem, in part because of the difficulty of specifying the appropriate phenotype to analyze and also because of the unknown degree of heterogeneity. Genetic markers are a special category of biological markers. In addition to conventional markers, the advent of "the new genetics" of recombinant DNA has meant that many more genetic markers (probes) are now available and that the day is not far off when the human genome will be extensively mapped. Considerable optimism exists about the future usefulness of genetic markers in detecting major gene effects and resolving problems of heterogeneity in schizophrenia.     

Environmental studies of schizophrenia through the prism of epigenetics

Traditionally, etiological research of schizophrenia has been focused on elucidating predisposing genes and environmental risk factors. While numerous putative environmental hazards have been suggested, inconsistencies and methodological limitations of epidemiological studies have made it difficult to identify even a single exogenous cause of schizophrenia. Furthermore, there is increasing evidence that environmental risk factors may not play as much of a significant role in schizophrenia as previously suspected. In this article, we argue that molecular epigenetic studies can overcome the complexities of traditional epidemiological studies and may become a productive line of research in understanding the nongenetic mechanisms of schizophrenia.