DNA methylation in white blood cells

Alterations in DNA methylation patterns, both at specific loci and overall in the genome, have been associated with many different health outcomes. In cancer and other diseases, most of these changes have been observed at the tissue level. Data on whether DNA methylation changes in white blood cells (WBC) can serve as a useful biomarker for different health outcomes are much more limited, but rapidly emerging. Epidemiologic studies have reported associations between global WBC methylation and several different cancers including cancers of the colon, bladder, stomach, breast and head and neck, as well as schizophrenia and myelodysplastic syndrome. Evidence for WBC methylation at specific loci and disease risk is more limited, but increasing. Differences in WBC DNA methylation by selected risk factors including demographic (age, gender, race), environmental exposures (benzene, persistent organic pollutants, lead, arsenic, and air pollution), and other risk factors (cigarette smoke, alcohol drinking, body size, physical activity and diet) have been observed in epidemiologic studies though the patterns are far from consistent. Challenges in inferences from the existing data are primarily due to the cross-sectional and small size of most studies to date as well as the differences in results across assay type and source of DNA. Large, prospective studies will be needed to understand whether changes in risk factors are associated with changes in DNA methylation patterns, and if changes in DNA methylation patterns are associated with changes in disease endpoints.     

The influence of illness‐related variables,personal resources and context‐related factors on real‐life functioning of people with schizophrenia

In people suffering from schizophrenia, major areas of everyday life are impaired, including independent living, productive activities and social relationships. Enhanced understanding of factors that hinder real‐life functioning is vital for treatments to translate into more positive outcomes. The goal of the present study was to identify predictors of real‐life functioning in people with schizophrenia, and to assess their relative contribution. Based on previous literature and clinical experience, several factors were selected and grouped into three categories: illness‐related variables, personal resources and context‐related factors. Some of these variables were never investigated before in relationship with real‐life functioning. In 921 patients with schizophrenia living in the community, we found that variables relevant to the disease, personal resources and social context explain 53.8% of real‐life functioning variance in a structural equation model. Neurocognition exhibited the strongest, though indirect, association with real‐life functioning. Positive symptoms and disorganization, as well as avolition, proved to have significant direct and indirect effects, while depression had no significant association and poor emotional expression was only indirectly and weakly related to real‐life functioning. Availability of a disability pension and access to social and family incentives also showed a significant direct association with functioning. Social cognition, functional capacity, resilience, internalized stigma and engagement with mental health services served as mediators. The observed complex associations among investigated predictors, mediators and real‐life functioning strongly suggest that integrated and personalized programs should be provided as standard treatment to people with schizophrenia.     

Comparative immunogenetics of autism and schizophrenia

Autism and schizophrenia are highly heritable neurodevelopmental disorders, each mediated by a diverse suite of genetic and environmental risk factors. Comorbidity and familial aggregation of such neurodevelopmental disorders with other disease-related conditions can provide important insights into their etiology. Epidemiological studies have documented reduced rates of rheumatoid arthritis, a systemic autoimmune condition, in schizophrenia, and recent work has shown increased rates of rheumatoid arthritis in first-degree relatives of autistic individuals, especially mothers. Advances in understanding the genetic basis of rheumatoid arthritis have shown that much of the genetic liability to this condition is due to risk and protective alleles at the HLA DRB1 locus. These data allow robust testing of the hypotheses that allelic variation at DRB1 pleiotropically modulates risk of rheumatoid arthritis, autism and schizophrenia. Systematic review of the literature indicates that reported associations of DRB1 variants with these three conditions are congruent with a pleiotropic model: DRB1*04 alleles have been associated with increased risk of rheumatoid arthritis and autism but decreased risk of schizophrenia, and DRB1*13 alleles have been associated with protection from rheumatoid arthritis and autism but higher risk of schizophrenia. These convergent findings from genetics and epidemiology imply that a subset of autism and schizophrenia cases may be underlain by genetically based neuroimmune alterations, and that analyses of the causes of risk and protective effects from DRB1 variants may provide new approaches to therapy.     

Variation in recombination rate across the genome: evidence and implications

Recent data from humans and other species provide convincing evidence of variation in recombination rate in different genomic regions. Comparison of physical and genetic maps reveals variation on a scale of megabases, with substantial differences between sexes. Recombination is often suppressed near centromeres and elevated near telomeres, but neither of these observations is true for all chromosomes. In humans, patterns of linkage disequilibrium and experimental measures of recombination from sperm-typing reveal dramatic hotspots of recombination on a scale of kilobases. Genome-wide variation in the amount of crossing-over may be due to variation in the density of hotspots, the intensity of hotspots, or both. Theoretical models of selection and linkage predict that genetic variation will be reduced in regions of low recombination, and this prediction is supported by data from several species. Heterogeneity in rates of crossing-over provides both an opportunity and a challenge for identifying disease genes: as associations occur in blocks, genomic regions containing disease loci may be identified with relatively few markers, yet identifying the causal mutations is unlikely to be achieved through associations alone.     

Clinically Significant Fatigue: Prevalence and Associated Factors in an International Sample of Adults with Multiple Sclerosis Recruited via the Internet

BackgroundFatigue contributes a significant burden of disease for people with multiple sclerosis (PwMS). Modifiable lifestyle factors have been recognized as having a role in a range of morbidity outcomes in PwMS. There is significant potential to prevent and treat fatigue in PwMS by addressing modifiable risk factors.ObjectivesTo explore the associations between clinically significant fatigue and demographic factors, clinical factors (health-related quality of life, disability and relapse rate) and modifiable lifestyle, disease-modifying drugs (DMD) and supplement use in a large international sample of PwMS.MethodsPwMS were recruited to the study via Web 2.0 platforms and completed a comprehensive survey measuring demographic, lifestyle and clinical characteristics, including health-related quality of life, disability, and relapse rate.ResultsOf 2469 participants with confirmed MS, 2138 (86.6%) completed a validated measure of clinically significant fatigue, the Fatigue Severity Scale. Participants were predominantly female from English speaking countries, with relatively high levels of education, and due to recruitment methods may have been highly pro-active about engaging in lifestyle management and self-help. Approximately two thirds of our sample (1402/2138; 65.6% (95% CI 63.7–67.7)) screened positive for clinically significant fatigue. Bivariate associations were present between clinically significant fatigue and several demographic, clinical, lifestyle, and medication variables. After controlling for level of disability and a range of stable socio-demographic variables, we found increased odds of fatigue associated with obesity, DMD use, poor diet, and reduced odds of fatigue with exercise, fish consumption, moderate alcohol use, and supplementation with vitamin D and flaxseed oil.ConclusionThis study supports strong and significant associations between clinically significant fatigue and modifiable lifestyle factors. Longitudinal follow-up of this sample may help clarify the contribution of reverse causation to our findings. Further research is required to explore these associations including randomized controlled trials of lifestyle interventions that may alleviate fatigue.     

Neurobiology of schizophrenia

With its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatments.     

Dopamine D4 receptors: beyond schizophrenia

Dopamine D4 receptors mediate a wide range of neuronal signal transduction cascades. Malfunctions of these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders, and their modification underlies the actions of many psychotropic drugs. Postmortem neuropathological and genetic studies provide inconclusive associations between D4 receptors and schizophrenia. Clinical trials of partially selective lead D4 antagonists have proved them to be ineffective against psychotic symptoms in patients diagnosed with schizophrenia. However, associations are emerging between D4 receptors and other neuropsychiatric disorders, including attention-deficit hyperactivity disorder as well as specific personality traits such as novelty seeking. Preclinical studies indicate that D4 receptors play a pivotal role in the cellular mechanisms of hyperactivity, impulsivity, and working memory. Accordingly, D4 receptors have broader implications for human illnesses than has been suggested by early focus on psychotic illness as a clinical target, and selective D4 agents may yield clinically useful drugs for several neuropsychiatric disorders that require improved treatments.     

Genomic and epigenomic instability, fragile sites, schizophrenia and autism

Increasing evidence links genomic and epigenomic instability, including multiple fragile sites regions to neuropsychiatric diseases including schizophrenia and autism. Cancer is the only other disease associated with multiple fragile site regions, and genome and epigenomic instability is a characteristic of cancer. Research on cancer is far more advanced than research on neuropsychiatric disease; hence, insight into neuropsychiatric disease may be derived from cancer research results. Towards this end, this article will review the evidence linking schizophrenia and other neuropsychiatric diseases (especially autism) to genomic and epigenomic instability, and fragile sites. The results of studies on genetic, epigenetic and environmental components of schizophrenia and autism point to the importance of the folate-methionine-transulfuration metabolic hub that is diseases also perturbed in cancer. The idea that the folate-methionine-transulfuration hub is important in neuropsychiatric is exciting because this hub present novel targets for drug development, suggests some drugs used in cancer may be useful in neuropsychiatric disease, and raises the possibility that nutrition interventions may influence the severity, presentation, or dynamics of disease.     

Genes,germs, and schizophrenia: an evolutionary perspective

Literature on schizophrenia and other mental illnesses has emphasized the compatibility of evidence with genetic causation without adequately considering alternative hypotheses of disease causation. Although some studies from the mid-20th century reported associations between certain pathogens and schizophrenia, only recently has the possibility of infectious causation of schizophrenia again become an active focus of research. Infectious causation of schizophrenia is still, however, generally regarded as less well demonstrated than genetic causation. This article evaluates the evidence that has been used to support genetic and infectious causation. Our consideration of infectious causation focuses on the protozoan Toxoplasma gondii but also assesses other pathogens that may contribute to the development of some of the illnesses currently categorized as schizophrenia. Although evidence generally accepted as demonstrating genetic causation can be readily explained by hypotheses of infectious causation, some of the evidence implicating infectious causation cannot be similarly explained by genetic causation. This asymmetry indicates that a scientific approach to the causation of schizophrenia needs to put a greater emphasis on tests that distinguish hypotheses of genetic causation from those of infectious causation.     

RELN基因启动子区SNP位点与精神分裂症的相关性分析

目前有很多证据证明RELN基因在世界人群中是一个精神分裂症的致病基因.基于之前报道过的RELN基因在精神分裂症患者中表达下降的事实,可以推测在RELN基因启动子区可能包含影响精神分裂症发生的多态位点.该研究分析了中国西南地区病例——对照人群中(940位患者和1369位正常人)RELN基因启动子区的3个单核苷酸多态性位点与精神分裂症的相关性.研究结果显示,这些多态位点都不与精神分裂症相关,表明RELN基因的致病位点并不在其启动子区.将前人研究结果与该研究结果进行综合分析(共2843个样本),结果仍不显著.因此,该研究表明,RELN基因启动子区的单核苷酸多态性位点在中国人群中并不与精神分裂症相关.     

Analysis of TBX1 variation in patients with psychotic and affective disorders

A significant portion of patients with 22q11 deletion syndrome (22q11DS) develop psychiatric disorders, including schizophrenia and other psychotic and affective symptoms, and the responsible gene/s are assumed to also play a significant role in the etiology of nonsyndromic psychiatric disease. The most common psychiatric diagnosis among patients with 22q11DS is schizophrenia, thought to result from neurotransmitter imbalances and also from disturbed brain development. Several genes in the 22q11 region with known or suspected roles in neurotransmitter metabolism have been analyzed in patients with isolated schizophrenia; however, their contribution to the disease remains controversial. Haploinsufficiency of the TBX1 gene has been shown to be sufficient to cause the core physical malformations associated with 22q11DS in mice and humans and via abnormal brain development could contribute to 22q11DS-related and isolated psychiatric disease. 22q11DS populations also have increased rates of psychiatric conditions other than schizophrenia, including mood disorders. We therefore analyzed variations at the TBX1 locus in a cohort of 446 white patients with psychiatric disorders relevant to 22q11DS and 436 ethnically matched controls. The main diagnoses included schizophrenia (n = 226), schizoaffective disorder (n = 67), bipolar disorder (n = 82), and major depressive disorder (n = 29). We genotyped nine tag SNPs in this sample but did not observe significant differences in allele or haplotype frequencies in any of the analyzed groups (all affected, schizophrenia and schizoaffective disorder, schizophrenia alone, and bipolar disorder and major depressive disorder) compared with the control group. Based on these results we conclude that TBX1 variation does not make a strong contribution to the genetic etiology of nonsyndromic forms of psychiatric disorders commonly seen in patients with 22q11DS.     

MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.     

MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.     

Linkage analysis of schizophrenia with five dopamine receptor genes in nine pedigrees

Alterations in dopamine neurotransmission have been strongly implicated in the pathogenesis of schizophrenia for nearly 2 decades. Recently, the genes for five dopamine receptors have been cloned and characterized, and genetic and physical map information has become available. Using these five loci as candidate genes, we have tested for genetic linkage to schizophrenia in nine multigenerational families which include multiple affected individuals. In addition to testing conservative disease models, we have used a neurophysiological indicator variable, the P50 auditory evoked response. Deficits in gating of the P50 response have been shown to segregate with schizophrenia in this sample and may identify carriers of gene(s) predisposing for schizophrenia. Linkage results were consistently negative, indicating that a defect at any of the actual receptor sites is unlikely to be a major contributor to schizophrenia in the nine families studied.     

HLA-B maternal-fetal genotype matching increases risk of schizophrenia

Schizophrenia and human leukocyte antigen (HLA) matching between couples or between mothers and offspring have independently been associated with prenatal/obstetric complications, including preeclampsia and low birth weight. Here, we report the results of a family-based candidate-gene study that brings together these two disparate lines of research by assessing maternal-fetal genotype matching at HLA-A, -B, and -DRB1 as a risk factor of schizophrenia. We used a conditional-likelihood modeling approach with a sample of 274 families that had at least one offspring with schizophrenia or a related spectrum disorder. A statistically significant HLA-B maternal-fetal genotype-matching effect on schizophrenia was demonstrated for female offspring (P=.01; parameter estimate 1.7 [95% confidence interval 1.22-2.49]). Because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se, these findings are consistent with the neurodevelopmental hypothesis of schizophrenia and with accumulating evidence that the prenatal period is involved in the origins of this disease. Our approach demonstrates how genetic markers can be used to characterize the biology of prenatal risk factors of schizophrenia.     

Bayesian Variable Selection for Multivariate Spatially Varying Coefficient Regression

Summary Physical activity has many well‐documented health benefits for cardiovascular fitness and weight control. For pregnant women, the American College of Obstetricians and Gynecologists currently recommends 30 minutes of moderate exercise on most, if not all, days; however, very few pregnant women achieve this level of activity. Traditionally, studies have focused on examining individual or interpersonal factors to identify predictors of physical activity. There is a renewed interest in whether characteristics of the physical environment in which we live and work may also influence physical activity levels. We consider one of the first studies of pregnant women that examines the impact of characteristics of the built environment on physical activity levels. Using a socioecologic framework, we study the associations between physical activity and several factors including personal characteristics, meteorological/air quality variables, and neighborhood characteristics for pregnant women in four counties of North Carolina. We simultaneously analyze six types of physical activity and investigate cross‐dependencies between these activity types. Exploratory analysis suggests that the associations are different in different regions. Therefore, we use a multivariate regression model with spatially varying regression coefficients. This model includes a regression parameter for each covariate at each spatial location. For our data with many predictors, some form of dimension reduction is clearly needed. We introduce a Bayesian variable selection procedure to identify subsets of important variables. Our stochastic search algorithm determines the probabilities that each covariate's effect is null, non‐null but constant across space, and spatially varying. We found that individual‐level covariates had a greater influence on women's activity levels than neighborhood environmental characteristics, and some individual‐level covariates had spatially varying associations with the activity levels of pregnant women.     

A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia

We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater “load” of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.     

Glutathione S-transferase M1 gene deletion may be associated with susceptibility to certain forms of schizophrenia

Recent studies have revealed that GSTM1 and M2 of the mu-class glutathione S-transferases catalyze a glutathione conjugate of catechol o-quinones including dopachrome, noradrenochrome, and adrenochrome under physiological conditions. Reduced or negative levels of activity amongst these enzymes would lead to an excess of neurotoxic compounds of catecholamine o-quinones. A defect in the mechanisms responsible for this form of detoxification may contribute to the development of certain forms of schizophrenia. We have performed a case-control study to explore the association between schizophrenia and polymorphism of the GSTM1 gene. DNA samples were obtained from 87 unrelated patients with schizophrenia who met the DSM-IV criteria for schizophrenia and from 176 control subjects. Individuals of both groups were ethnically Japanese and were from the same district. GSTM1 polymorphism was determined using the polymerase chain reaction method. The frequency of the GSTM1*0 allele was significantly higher amongst the patients with schizophrenia compared to controls (P = 0.0075). Moreover, the incidence of the GSTM1*0 was significantly higher amongst the schizophrenic patients classified as disorganized type (P = 0.0008), relative to the control sample. Our findings suggest that the GSTM1*0 is associated with an increased susceptibility to schizophrenia, particularly disorganized type of the disease. It is therefore likely that the GSTM1 gene deletion constitutes to vulnerability for disease states of this kind, rather than being the direct cause of schizophrenic conditions.     

Schizophrenia Genetics

Schizophrenia is a complex multifactorial disease, in most cases manifested as a result of the interaction of genetic and psychological factors, as well as certain environmental conditions. However, genetic factors certainly play a determining role in the predisposition to schizophrenia. The coefficient of heritability of schizophrenia is about 80%, which is typical of the most highly inherited multifactorial diseases. This review presents the results of the latest world studies of genetic factors in the development of schizophrenia, including epigenetic, genome-wide association studies, and next generation sequencing.     

Developmental vitamin D deficiency and schizophrenia: the role of animal models

Schizophrenia is a debilitating neuropsychiatric disorder that affects 1% of the US population. Based on twin and genome‐wide association studies, it is clear that both genetics and environmental factors increase the risk for developing schizophrenia. Moreover, there is evidence that conditions in utero, either alone or in concert with genetic factors, may alter neurodevelopment and lead to an increased risk for schizophrenia. There has been progress in identifying genetic loci and environmental exposures that increase risk, but there are still considerable gaps in our knowledge. Furthermore, very little is known about the specific neurodevelopmental mechanisms upon which genetics and the environment act to increase disposition to developing schizophrenia in adulthood. Vitamin D deficiency during the perinatal period has been hypothesized to increase risk for schizophrenia in humans. The developmental vitamin D (DVD) deficiency hypothesis of schizophrenia arises from the observation that disease risk is increased in individuals who are born in winter or spring, live further from the equator or live in urban vs. rural settings. These environments result in less exposure to sunlight, thereby reducing the initial steps in the production of vitamin D. Rodent models have been developed to characterize the behavioral and developmental effects of DVD deficiency. This review focuses on these animal models and discusses the current knowledge of the role of DVD deficiency in altering behavior and neurobiology relevant to schizophrenia.