Genome scan meta-analysis of schizophrenia and bipolar disorder,part III: Bipolar disorder

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for “very narrow” (i.e., BP-I and schizoaffective disorder–BP) and “narrow” (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A “broad” model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.     

Genome scan meta-analysis of schizophrenia and bipolar disorder,part II: Schizophrenia

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.     

Genome scan meta-analysis of schizophrenia and bipolar disorder,part I: Methods and power analysis

This is the first of three articles on a meta-analysis of genome scans of schizophrenia (SCZ) and bipolar disorder (BPD) that uses the rank-based genome scan meta-analysis (GSMA) method. Here we used simulation to determine the power of GSMA to detect linkage and to identify thresholds of significance. We simulated replicates resembling the SCZ data set (20 scans; 1,208 pedigrees) and two BPD data sets using very narrow (9 scans; 347 pedigrees) and narrow (14 scans; 512 pedigrees) diagnoses. Samples were approximated by sets of affected sibling pairs with incomplete parental data. Genotypes were simulated and nonparametric linkage (NPL) scores computed for 20 180-cM chromosomes, each containing six 30-cM bins, with three markers/bin (or two, for some scans). Genomes contained 0, 1, 5, or 10 linked loci, and we assumed relative risk to siblings (lambda(sibs)) values of 1.15, 1.2, 1.3, or 1.4. For each replicate, bins were ranked within-study by maximum NPL scores, and the ranks were averaged (R(avg)) across scans. Analyses were repeated with weighted ranks ((sqrt)N[genotyped cases] for each scan). Two P values were determined for each R(avg): P(AvgRnk) (the pointwise probability) and P(ord) (the probability, given the bin's place in the order of average ranks). GSMA detected linkage with power comparable to or greater than the underlying NPL scores. Weighting for sample size increased power. When no genomewide significant P values were observed, the presence of linkage could be inferred from the number of bins with nominally significant P(AvgRnk), P(ord), or (most powerfully) both. The results suggest that GSMA can detect linkage across multiple genome scans.     

The genetic variation of RELN expression in schizophrenia and bipolar disorder

Reelin plays an important role in the development and function of the brain and has been linked to different neuropsychiatric diseases. To further clarify the connection between reelin and psychiatric disorders, we studied the factors that influence the expression of reelin gene (RELN) and its different isoforms. We examined the total expression of RELN, allelic expression, and two alternative RELN isoforms in postmortem brain samples from patients with schizophrenia and bipolar disorder, as well as unaffected controls. We did not find a significant reduction in the total expression of RELN in schizophrenia or bipolar disorder. However, we did find a significant reduction of the proportion of the short RELN isoform, missing the C-terminal region in bipolar disorder, and imbalance in the allelic expression of RELN in schizophrenia. In addition, we tested the association between variation in RELN expression and rs7341475, an intronic SNP that was found to be associated with schizophrenia in women. We did not find an association between rs7341474 and the total expression of RELN either in women or in the entire sample. However, we observed a nominally significant effect of genotype-by-sex interaction on the variation in microexon skipping. Women with the risk genotype of rs7341475 (GG) had a higher proportion of microexon skipping, which is the isoform predominant in tissues outside the brain, while men had the opposite trend. Finally, we tested 83 SNPs in the gene region for association with expression variation of RELN, but none were significant. Our study further supports the connection between RELN dysfunction and psychiatric disorders, and provides a possible functional role for a schizophrenia associated SNP. Nevertheless, the positive associations observed in this study needs further replication as it may have implications for understanding the biological causes of schizophrenia and bipolar disorder.     

Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder

Schizophrenia, schizoaffective disorder, and bipolar disorder are common psychiatric disorders with high heritabilities and variable phenotypes. The Disrupted in Schizophrenia 1 (DISC1) gene, on chromosome 1q42, was originally discovered and linked to schizophrenia in a Scottish kindred carrying a balanced translocation that disrupts DISC1 and DISC2. More recently, DISC1 was linked to schizophrenia, broadly defined, in the general Finnish population, through the undertransmission to affected women of a common haplotype from the region of intron 1/exon 2. We present data from a case-control study of a North American white population, confirming the underrepresentation of a common haplotype of the intron 1/exon 2 region in individuals with schizoaffective disorder. Multiple haplotypes contained within four haplotype blocks extending between exon 1 and exon 9 are associated with schizophrenia, schizoaffective disorder, and bipolar disorder. We also find overrepresentation of the exon 9 missense allele Phe607 in schizoaffective disorder. These data support the idea that these apparently distinct disorders have at least a partially convergent etiology and that variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders.     

Novel loci and potential mechanisms of major depressive disorder,bipolar disorder,and schizophrenia

Science China Life Sciences - Different psychiatric disorders share genetic relationships and pleiotropic loci to certain extent. We integrated and analyzed datasets related to major depressive...     

A candidate gene for schizophrenia and bipolar disorder

Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder?Chandy, K.G. et al. (1998)Mol. Psychiatr. 3, 32–37     

Genetics of schizophrenia and bipolar disorder: recent success of linkage studies with evidence of specific and shared susceptibility loci

Results claiming linkage on two chromosomes for schizophrenia (SZ) and bipolar affective disorder (BP) were prematurely published in Nature at the end of the '80s. This ended up into disappointment. The knowledge accumulated from the first generation of unsuccessful molecular genetics studies of SZ and BP provided a stronger basis for the following generation of linkage studies that are now yielding encouraging converging results. Hence, we report several genomics susceptibility loci for SZ and BP, some of them being probably shared by the two major psychiatric illnesses whereas others could be specific to each.     

DNA methylation changes in schizophrenia and bipolar disorder

The etiology of the major psychotic disorders, including schizophrenia and bipolar disorder, remains poorly understood. Postmortem brain studies have revealed altered expression of multiple mRNAs, affecting neurotransmission, metabolism, myelination and other functions. Epigenetic mechanisms could be involved, because for a limited number of genes, the alterations on the mRNA level were linked to inverse DNA methylation changes at sites of the corresponding promoters. However, results from independent studies have been inconsistent and when expressed in quantitative terms, disease-related methylation changes appeared to be comparatively subtle. A recent study identified approximately 100 loci with altered CpG methylation in schizophrenia or bipolar disorder, the majority of which were gender-specific. Additional work will be necessary to clarify the origin and timing of these methylation changes in psychosis, and to determine the specific cell types affected in CNS.     

Comparison of hippocampal volumes in schizophrenia, schizoaffective and bipolar disorder

The reduction of hippocampal volume was frequently reported in schizophrenia, but not in bipolar disorder This volume reduction is associated with clinical features of schizophrenia, in particular with working and verbal memory impairments. Schizoaffective disorder, as a specific disorder sharing clinical features of both schizophrenia and bipolar disorder is rarely analyzed as a separate disorder in neurobiological studies. The aim of this study was to compare hippocampal volumes in separate groups of patients with schizophrenia, schizoaffective and bipolar disorder. Hippocampal volumes were estimated using high resolution magnetic resonance imaging in 60 subjects, 15 subjects in each patient and one healthy volunteer (control) group. There were no significant differences in hippocampal volume between bipolar disorder and control group. Hippocampal volume was statistically significantly reduced in the group of patients with schizophrenia and schizoaffective disorder, compared to either bipolar disorder or control group, thus supporting the hypothesis that hippocampal volume reduction could be considered as a possible neurobiological basis for clinical aspects of schizophrenia and schizoaffective disorder associated with working and verbal memory impairment.     

High throughput lipidomic profiling of schizophrenia and bipolar disorder brain tissue reveals alterations of free fatty acids, phosphatidylcholines, and ceramides

A mass spectrometry based high throughput approach was employed to profile white and gray matter lipid levels in the prefrontal cortex (Brodmann area 9) of 45 subjects including 15 schizophrenia and 15 bipolar disorder patients as well as 15 controls samples. We found statistically significant alterations in levels of free fatty acids and phosphatidylcholine in gray and white matter of both schizophrenia and bipolar disorder samples compared to controls. Also, ceramides were identified to be significantly increased in white matter of both neuropsychiatric disorders as compared to control levels. The patient cohort investigated in this study includes a number of drug naive as well as untreated patients, allowing the assessment of drug effects on lipid levels. Our findings indicate that while gray matter phosphatidylcholine levels were influenced by antipsychotic medication, this was not the case for phosphatidylcholine levels in white matter. Changes in free fatty acids or ceramides in either white or gray matter also did not appear to be influenced by antipsychotic treatment. To assess lipid profiles in the living patient, we also profiled lipids of 40 red blood cell samples, including 7 samples from drug naive first onset patients. We found significant alterations in the concentrations of free fatty acids as well as ceramide. Overall, our findings suggest that lipid abnormalities may be a disease intrinsic feature of both schizophrenia and bipolar disorder reflected by significant changes in the central nervous system as well as peripheral tissues.     

Dysregulation of neural calcium signaling in Alzheimer disease,bipolar disorder and schizophrenia

Neurons have highly developed Ca²⁺ signaling systems responsible for regulating a large number of neural functions such as the control of brain rhythms, information processing and the changes in synaptic plasticity that underpin learning and memory. The tonic excitatory drive, which is activated by the ascending arousal system, is particularly important for processes such as sensory perception, cognition and consciousness. The Ca²⁺ signaling pathway is a key component of this arousal system that regulates the neuronal excitability responsible for controlling the neural brain rhythms required for information processing and cognition. Dysregulation of the Ca²⁺ signaling pathway responsible for many of these neuronal processes has been implicated in the development of some of the major neural diseases in man such as Alzheimer disease, bipolar disorder and schizophrenia. Various treatments, which are known to act by reducing the activity of Ca²⁺ signaling, have proved successful in alleviating the symptoms of some of these neural diseases.     

SIRT1 gene, schizophrenia and bipolar disorder in the Japanese population: an association study

Several lines of evidence suggest that alterations in circadian rhythms might be associated with the pathophysiology of psychiatric disorders such as schizophrenia and bipolar disorder (BP). A recent study reported that SIRT1 is a molecule that plays an important role in the circadian clock system. Therefore, to evaluate the association among the SIRT1 gene, schizophrenia and BP, we conducted a case-control study of Japanese population samples (1158 schizophrenia patients, 1008 BP patients and 2127 controls) with four tagging SNPs (rs12778366, rs2273773, rs4746720 and rs10997875) in the SIRT1 gene. Marker-trait association analysis was used to evaluate the allele and the genotype association with the χ(2) test, and haplotype association analysis was evaluated with a likelihood ratio test. We showed an association between rs4746720 in the SIRT1 gene and schizophrenia in the allele and the genotype analysis. However, the significance of these associations did not survive after Bonferroni's correction for multiple testing. On the other hand, the SIRT1 gene was associated with Japanese schizophrenia in a haplotype-wise analysis (global P(all markers) = 4.89 × 10(-15)). Also, four tagging SNPs in the SIRT1 gene were not associated with BP. In conclusion, the SIRT1 gene may play an important role in the pathophysiology of schizophrenia in the Japanese population.     

Progranulin gene variability and plasma levels in bipolar disorder and schizophrenia

Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n = 271) or BPD (n = 237) as compared with 574 age-, gender- and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls.A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.2 versus 34.2%, P<0.001, OR:0.63, 95%CI:0.49–0.80), rs4792938 (30.7 versus 39.7%, P = 0.005, OR: 0.70, 95%CI: 0.55–0.89) and rs5848 (30.3 versus 36.8, P = 0.007, OR: 0.71, 95%CI: 0.56–0.91). Mean±SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69±3.97 and 116.14±5.80 ng/ml, respectively, versus 180.81±18.39 ng/ml P<0.001) and were not correlated with age.In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm these preliminary results.     

Diagnosis of bipolar disorders: focus on bipolar disorder I and bipolar disorder II

Bipolar disorders are currently divided into 4 entities: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not otherwise specified, as described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). These subtypes of bipolar disorders cover a spectrum of severities, frequencies, and durations of manic and depressive symptoms. The differential diagnosis among these and with regard to other disorders with similar symptom features remains the foundation for treatment of bipolar disorders. It is clear that much diversity exists within these major subtypes, such that designations like "rapid cycling" and "bipolar III" are being put forward and probed for clinical relevance. Some of the concerns and advantages of including these less-established manifestations of bipolar disorders in our diagnostic thinking are discussed here, and the utility and drawbacks of our current diagnostic protocols are considered.     

High frequencies of de novo CNVs in bipolar disorder and schizophrenia

While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n?= 185), schizophrenia (n?= 177), and healthy controls (n?= 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR?= 4.8 [1.4,16.0], p?= 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR?= 6.3 [1.7,22.6], p?= 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR?= 5.0 [1.5,16.8], p?= 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.     

Peptoid architectures: elaboration, actuation, and application

Peptoids are peptidomimetic oligomers composed of N-substituted glycine units. Their convenient synthesis enables strict control over the sequence of highly diverse monomers and is capable of generating extensive compound libraries. Recent studies are beginning to explore the relationship between peptoid sequence, structure and function. We describe new approaches to direct the conformation of the peptoid backbone, leading to secondary structures such as helices, loops, and turns. These advances are enabling the discovery of bioactive peptoids and will establish modules for the design and assembly of protein mimetics.     

Multivariate survival models induced by genetic frailties,with application to linkage analysis

We derive a multivariate survival model for age of onset data of a sibship from an additive genetic gamma frailty model constructed basing on the inheritance vectors, and investigate the properties of this model. Based on this model, we propose a retrospective likelihood approach for genetic linkage analysis using sibship data. This test is an allele-sharing-based test, and does not require specification of genetic models or the penetrance functions. This new approach can incorporate both affected and unaffected sibs, environmental covariates and age of onset or age at censoring information and, therefore, provides a practical solution for mapping genes for complex diseases with variable age of onset. Small simulation study indicates that the proposed method performs better than the commonly used allele-sharing-based methods for linkage analysis, especially when the population disease rate is high. We applied this method to a type 1 diabetes sib pair data set and a small breast cancer data set. Both simulated and real data sets also indicate that the method is relatively robust to the misspecification to the baseline hazard function.