Linkage analysis of Schizophrenia: Challenges and promise

Abstract

Schizophrenia is a serious mental illness affecting nearly 1 per cent of the general population. Family, twin, and adoption studies suggest that genetics plays a major role in the etiology of schizophrenia. The inheritance pattern appears complex, similar to that of other common conditions like heart disease. To uncover a causal genetic factor, researchers have recently begun to apply a linkage analysis strategy to schizophrenia. Early results suggest that there are many challenges facing scientists who undertake schizophrenia genetics research. While one study has shown significant linkage of schizophrenia to a region on chromosome 5, several other studies have not found linkage to this area. The likelihood that there are several major genes predisposing to the illness and uncertainties about inheritance patterns and diagnostic boundaries are potential difficulties to overcome. Many more families need to be studied, and creative complementary research strategies pursued, to achieve the potential success offered by a genetic linkage approach.     

Schizophrenia and Violence: Systematic Review and Meta-Analysis

Background

Although expert opinion has asserted that there is an increased risk of violence in individuals with schizophrenia and other psychoses, there is substantial heterogeneity between studies reporting risk of violence, and uncertainty over the causes of this heterogeneity. We undertook a systematic review of studies that report on associations between violence and schizophrenia and other psychoses. In addition, we conducted a systematic review of investigations that reported on risk of homicide in individuals with schizophrenia and other psychoses.

Methods and Findings

Bibliographic databases and reference lists were searched from 1970 to February 2009 for studies that reported on risks of interpersonal violence and/or violent criminality in individuals with schizophrenia and other psychoses compared with general population samples. These data were meta-analysed and odds ratios (ORs) were pooled using random-effects models. Ten demographic and clinical variables were extracted from each study to test for any observed heterogeneity in the risk estimates. We identified 20 individual studies reporting data from 18,423 individuals with schizophrenia and other psychoses. In men, ORs for the comparison of violence in those with schizophrenia and other psychoses with those without mental disorders varied from 1 to 7 with substantial heterogeneity (I ² = 86%). In women, ORs ranged from 4 to 29 with substantial heterogeneity (I ² = 85%). The effect of comorbid substance abuse was marked with the random-effects ORs of 2.1 (95% confidence interval [CI] 1.7–2.7) without comorbidity, and an OR of 8.9 (95% CI 5.4–14.7) with comorbidity (p<0.001 on metaregression). Risk estimates of violence in individuals with substance abuse (but without psychosis) were similar to those in individuals with psychosis with substance abuse comorbidity, and higher than all studies with psychosis irrespective of comorbidity. Choice of outcome measure, whether the sample was diagnosed with schizophrenia or with nonschizophrenic psychoses, study location, or study period were not significantly associated with risk estimates on subgroup or metaregression analysis. Further research is necessary to establish whether longitudinal designs were associated with lower risk estimates. The risk for homicide was increased in individuals with psychosis (with and without comorbid substance abuse) compared with general population controls (random-effects OR = 19.5, 95% CI 14.7–25.8).

Conclusions

Schizophrenia and other psychoses are associated with violence and violent offending, particularly homicide. However, most of the excess risk appears to be mediated by substance abuse comorbidity. The risk in these patients with comorbidity is similar to that for substance abuse without psychosis. Public health strategies for violence reduction could consider focusing on the primary and secondary prevention of substance abuse. Please see later in the article for Editors'' Summary     

The importance of modelling heterogeneity in complex disease: application to NIMH Schizophrenia Genetics Initiative data

As for other complex diseases, linkage analyses of schizophrenia (SZ) have produced evidence for numerous chromosomal regions, with inconsistent results reported across studies. The presence of locus heterogeneity appears likely and may reduce the power of linkage analyses if homogeneity is assumed. In addition, when multiple heterogeneous datasets are pooled, inter-sample variation in the proportion of linked families () may diminish the power of the pooled sample to detect susceptibility loci, in spite of the larger sample size obtained. We compare the significance of linkage findings obtained using allele-sharing LOD scores (LOD_exp)—which assume homogeneity—and heterogeneity LOD scores (HLOD) in European American and African American NIMH SZ families. We also pool these two samples and evaluate the relative power of the LOD_exp and two different heterogeneity statistics. One of these (HLOD-P) estimates the heterogeneity parameter only in aggregate data, while the second (HLOD-S) determines separately for each sample. In separate and combined data, we show consistently improved performance of HLOD scores over LOD_exp. Notably, genome-wide significant evidence for linkage is obtained at chromosome 10p in the European American sample using a recessive HLOD score. When the two samples are combined, linkage at the 10p locus also achieves genome-wide significance under HLOD-S, but not HLOD-P. Using HLOD-S, improved evidence for linkage was also obtained for a previously reported region on chromosome 15q. In linkage analyses of complex disease, power may be maximised by routinely modelling locus heterogeneity within individual datasets, even when multiple datasets are combined to form larger samples.     

Citing a Data Repository: A Case Study of the Protein Data Bank

The Protein Data Bank (PDB) is the worldwide repository of 3D structures of proteins, nucleic acids and complex assemblies. The PDB’s large corpus of data (> 100,000 structures) and related citations provide a well-organized and extensive test set for developing and understanding data citation and access metrics. In this paper, we present a systematic investigation of how authors cite PDB as a data repository. We describe a novel metric based on information cascade constructed by exploring the citation network to measure influence between competing works and apply that to analyze different data citation practices to PDB. Based on this new metric, we found that the original publication of RCSB PDB in the year 2000 continues to attract most citations though many follow-up updates were published. None of these follow-up publications by members of the wwPDB organization can compete with the original publication in terms of citations and influence. Meanwhile, authors increasingly choose to use URLs of PDB in the text instead of citing PDB papers, leading to disruption of the growth of the literature citations. A comparison of data usage statistics and paper citations shows that PDB Web access is highly correlated with URL mentions in the text. The results reveal the trend of how authors cite a biomedical data repository and may provide useful insight of how to measure the impact of a data repository.     

Linkage of Familial Schizophrenia to Chromosome 13q32

Over the past 4 years, a number of investigators have reported findings suggestive of linkage to schizophrenia, with markers on chromosomes 13q32 and 8p21, with one recent study by Blouin et al. reporting significant linkage to these regions. As part of an ongoing genome scan, we evaluated microsatellite markers spanning chromosomes 8 and 13, for linkage to schizophrenia, in 21 extended Canadian families. Families were analyzed under autosomal dominant and recessive models, with broad and narrow definitions of schizophrenia. All models produced positive LOD scores with markers on 13q, with higher scores under the recessive models. The maximum three-point LOD scores were obtained under the recessive-broad model: 3.92 at recombination fraction (theta).1 with D13S793, under homogeneity, and 4.42 with alpha=.65 and straight theta=0 with D13S793, under heterogeneity. Positive LOD scores were also obtained, under all models, for markers on 8p. Although a maximum two-point LOD score of 3.49 was obtained under the dominant-narrow model with D8S136 at straight theta=0.1, multipoint analysis with closely flanking markers reduced the maximum LOD score in this region to 2. 13. These results provide independent significant evidence of linkage of a schizophrenia-susceptibility locus to markers on 13q32 and support the presence of a second susceptibility locus on 8p21.     

Impact of Neoadjuvant Chemotherapy on Immediate Breast Reconstruction: A Meta-Analysis

Objective

The objective of this study was to perform a meta-analysis of published studies for evaluating the impact of neoadjuvant chemotherapy (NAC) on immediate breast reconstruction.

Methods

We searched medical databases to identify appropriate studies that assessed the impact of NAC on immediate breast reconstruction from the inception of this technique through April 2013. We then performed a meta-analysis of these studies.

Results

Our searches identified 11 studies among 1,840 citations. In the meta-analysis, NAC did not increase the overall rate of complications after immediate breast reconstruction (odds ratio [OR] = 0.59; 95% confidence interval[CI] = 0.38–0.91). The complication rate was also unaffected by NAC when we considered infections (OR = 0.82; 95% CI = 0.46–1.45), hematomas (OR = 1.35; 95% CI = 0.57–3.21), and seromas (OR = 0.77; 95% CI = 0.23–2.55). Additionally, expander or implant loss did not significantly increase in patients after NAC (OR = 1.59; 95% CI = 0.91–2.79). Only 2 studies (202 procedures) had reported total autologous flap loss, and they were included in our analysis; both studies found no association between NAC and total flap loss.

Conclusion

Our analysis suggests that NAC does not increase the complication rate after immediate breast reconstruction. For appropriately selected patients, immediate breast reconstruction following NAC is a safe procedure. The best way to study this issue in the future is to conduct a multicenter prospective study with a longer follow-up period and more clearly defined parameters.     

Beware of Primate Life History Data: A Plea for Data Standards and a Repository

Life history variables such as the age at first reproduction and the interval between consecutive births are measures of investment in growth and reproduction in a particular population or species. As such they allow for meaningful comparisons of the speed of growth and reproduction between species and between larger taxa. Especially in primates such life history research has far reaching implications and has led for instance to the “grandmother hypothesis”. Other links have been proposed with respect to dietary adaptations: Because protein is essential for growth and one of the primary sources of protein, leaves, occurs much less seasonally than fruits, it has been predicted that folivorous primates should grow faster compared to frugivorous ones. However, when comparing folivorous Asian colobines with frugivorous Asian macaques we recently documented a longer, instead of a shorter gestation length in folivores while age at first reproduction and interbirth interval did not differ. This supports earlier findings for Malagasy lemurs in which all life history variables tested were significantly longer in folivores compared to frugivores. Wondering why these trends were not apparent sooner, we tried to reconstruct our results for Asian primates with data from four popular life history compilations. However, this attempt failed; even the basic, allometric relationship with adult female body mass that is typical for life history variables could not be recovered. This negative result hints at severe problems with data quality. Here we show that data quality can be improved significantly by standardizing the variables and by controlling for factors such as nutritional conditions or infant mortality. Ideally, in the future, revised primate life history data should be collated in a central database accessible to everybody. In the long run such an initiative should be expanded to include all mammalian species.     

Linkage Disequilibrium in Humans: Models and Data

In this review, we describe recent empirical and theoretical work on the extent of linkage disequilibrium (LD) in the human genome, comparing the predictions of simple population-genetic models to available data. Several studies report significant LD over distances longer than those predicted by standard models, whereas some data from short, intergenic regions show less LD than would be expected. The apparent discrepancies between theory and data present a challenge-both to modelers and to human geneticists-to identify which important features are missing from our understanding of the biological processes that give rise to LD. Salient features may include demographic complications such as recent admixture, as well as genetic factors such as local variation in recombination rates, gene conversion, and the potential segregation of inversions. We also outline some implications that the emerging patterns of LD have for association-mapping strategies. In particular, we discuss what marker densities might be necessary for genomewide association scans.     

Pollution and Its Impact on Wild Animals: A Meta-Analysis on Oxidative Stress

Oxidative stress is the unifying feature underlying the toxicity of anthropogenic pollution (e.g., heavy metals, polycyclic aromatic hydrocarbons, and nitrogen-oxides) and the ultimate culprit in the development of many diseases. Yet, there has been no attempt to summarize the published data on wild terrestrial animals to reveal general trends regarding the effects of pollution on oxidative stress. The main findings of this meta-analysis reveal that, as predicted, there is an overall increase in oxidative stress when exposed to pollution. This is mainly due to a weak overall increase of oxidative damages, although there is some variation across taxa. The reduced form of glutathione (GSH) and its associated enzymes are the most reliable biomarkers. This result is important when choosing biomarkers and when using less-invasive sampling of endangered species, or for longitudinal approaches. To be able to predict future population outcomes, possible treatments, but also evolutionary responses to a changing environment, a greater integration of biotic factors such as temperature, bioavailability of toxic elements, and species-specific responses are needed.     

Apolipoprotein E Polymorphism and Colorectal Neoplasm: Results from a Meta-Analysis

To investigate the relationship of Apolipoprotein E (APOE) gene polymorphism to colorectal neoplasia (CRN), we performed a systematic review and meta-analysis. Eligible studies were identified through a systematic literature review from PubMed, EMBASE, and the Science Citation Index up to February 2014. A combined analysis was performed, followed by a subgroup analyses stratified by the study design. We used data collected from 8 prospective studies involving respectively a total of 9243 participants and 4310 CRN cases which including 438 patients with colorectal adenoma (CRA), and 3873 patients with colorectal carcinoma (CRC). The pooled data from this meta-analysis indicated there was no significant association between APOE polymorphism and CRN (ε2: P = 0.51, OR 1.04 95% CI 0.93 to 1.16; ε4: P = 0.72, OR 0.98 95% CI 0.90 to 1.07). Interestingly, subgroup analysis demonstrated there was a significant decreased risk for proximal CRN in patients with APOE ε4 (P = 0.0007, OR 0.52 95% CI 0.35 to 0.76). Data showed no significant association between APOE genotype and overall CRN. However, compared with those carry APOE ε3 alleles, persons with APOE ε4 genotype have significant decreased risk suffering from proximal CRN but not from distal CRN.     

Impact of Smoking on the Risk of Pancreatitis: A Systematic Review and Meta-Analysis

Background and objective

Cigarette smoking may increase the risk of developing pancreatic cancer, although its impact on pancreatitis has only been discerned in recent years. However, the results of previous studies differ. We performed a meta-analysis to provide a quantitative pooled risk estimate of the association of cigarette smoking with pancreatitis.

Method

A literature search of the MEDLINE and Embase databases was conducted, and studies were selected that investigated the association of cigarette smoking with pancreatitis. Summary relative risks (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model.

Results

Twenty-two studies were included. The summary RRs (95% CI) associated with ever, current and former smokers for acute and chronic pancreatitis (AP/CP) were as follows: 1.51 (1.10, 2.07)/3.00 (1.46, 6.17), 1.42 (1.08, 1.87)/2.72 (1.74, 4.24), and 1.22 (0.99, 1.52)/1.27 (1.00, 1.62), respectively. Moreover, studies that analyzed both AP and CP were also summarized: 1.73 (1.18, 2.54) for ever smokers, 1.67 (1.03, 2.68) for current smokers and 1.56 (1.16, 2.11) for former smokers, respectively. There was no evidence of publication bias across the studies.

Conclusion

The evidence suggests a positive association of cigarette smoking with the development of pancreatitis. It is possible that smoking cessation may be a useful strategy for the management of pancreatitis.     

Association of PDE4B Polymorphisms with Susceptibility to Schizophrenia: A Meta-Analysis of Case-Control Studies

Background

The PDE4B single nucleotide polymorphisms (SNPs) have been reported to be associated with schizophrenia risk. However, current findings are ambiguous or even conflicting. To better facilitate the understanding the genetic role played by PDE4B in susceptibility to schizophrenia, we collected currently available data and conducted this meta-analysis.

Methods

A comprehensive electronic literature searching of PubMed, Embase, Web of Science and Cochrane Library was performed. The association between PDE4B SNPs and schizophrenia was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant and recessive genetic models. The random effects model was utilized when high between-study heterogeneity (I² > 50%) existed, otherwise the fixed effects model was used.

Results

Five studies comprising 2376 schizophrenia patients and 3093 controls were finally included for meta-analysis. The rs1040716 was statistically significantly associated with schizophrenia risk in Asian and Caucasian populations under dominant model (OR = 0.87, 95% CI: 0.76–0.99, P = 0.04). The rs2180335 was significantly related with schizophrenia risk in Asian populations under allelic (OR = 0.82, 95% CI: 0.72–0.93, P = 0.003) and dominant (OR = 0.75, 95% CI: 0.64–0.88, P < 0.001) models. A significant association was also observed between rs4320761 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.75–1.00, P = 0.048). In addition, a strong association tendency was found between rs6588190 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.76–1.00, P = 0.055).

Conclusion

This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. However, due to limited sample size, more large-scale, multi-racial association studies are needed to further clarify the genetic association between various PDE4B variants and schizophrenia.     

Workplace Bullying and Mental Health: A Meta-Analysis on Cross-Sectional and Longitudinal Data

Background

A growing body of research has confirmed that workplace bullying is a source of distress and poor mental health. Here we summarize the cross-sectional and longitudinal literature on these associations.

Methods

Systematic review and meta-analyses on the relation between workplace bullying and mental health.

Results

The cross-sectional data (65 effect sizes, N = 115.783) showed positive associations between workplace bullying and symptoms of depression (r = .28, 95% CI = .23–.34), anxiety (r = .34, 95% CI = .29–.40) and stress-related psychological complaints (r = .37, 95% CI = .30–.44). Pooling the literature that investigated longitudinal relationships (26 effect sizes, N = 54.450) showed that workplace bullying was related to mental health complaints over time (r = 0.21, 95% CI = 0.13–0.21). Interestingly, baseline mental health problems were associated with subsequent exposure to workplace bullying (r = 0.18, 95% CI = 0.10–0.27; 11 effect sizes, N = 27.028).

Limitations

All data were self-reported, raising the possibility of reporting- and response set bias.

Conclusions

Workplace bullying is consistently, and in a bi-directional manner, associated with reduced mental health. This may call for intervention strategies against bullying at work.     

The Impact of the Choice of Data Source in Record Linkage Studies Estimating Mortality in Venous Thromboembolism

Linked electronic healthcare databases are increasingly being used in observational research. The objective of this study was to investigate the impact of the choice of data source in estimating mortality following VTE, with a secondary aim to investigate the influence of the denominator definition. We used the UK Clinical Practice Research Datalink (CPRD) to identify patients aged 18+ with venous thromboembolism (VTE). Multiple cohorts were identified in order to assess how mortality rates differed with a range of data sources. For each of the cohorts, incidence rates per 1,000 person years (/1000py) and relative rates (RRs) of all-cause mortality were calculated. The lowest mortality rate was found when only primary care data were used for both the exposure (VTE) and the outcome (death) (108.4/1000py). The highest mortality rate was found for patients diagnosed in secondary care (237.2/1000py). When linked primary and secondary care data were included for eligible patients and for the overlapping period of data collection, a mortality rate of 173.2/1000py was found. Sensitivity analyses varying the denominator definition provided a range of results (140.6–164.3/1000py). The relative rates of mortality by gender and age were comparable across all cohorts. Depending on the choice of data source, the population studied may be different. This may have substantial impact on the main findings, in particular on incidence rates of mortality following VTE.     

Systematic Review and Meta-Analysis of Circulating S100B Blood Levels in Schizophrenia

S100B is a calcium-binding protein secreted in central nervous system from astrocytes and other glia cells. High blood S100B levels have been linked to brain damage and psychiatric disorders. S100B levels have been reported to be higher in schizophrenics than healthy controls. To quantify the relationship between S100B blood levels and schizophrenia a systematic literature review of case-control studies published on this topic within July 3^rd 2014 was carried out using three bibliographic databases: Medline, Scopus and Web of Science. Studies reporting mean and standard deviation of S100B blood levels both in cases and controls were included in the meta-analysis. The meta-Mean Ratio (mMR) of S100B blood levels in cases compared to controls was used as a measure of effect along with its 95% Confidence Intervals (CI). 20 studies were included totaling for 994 cases and 785 controls. Schizophrenia patients showed 76% higher S100B blood levels than controls with mMR = 1.76 95% CI: 1.44–2.15. No difference could be found between drug-free patients with mMR = 1.84 95%CI: 1.24–2.74 and patients on antipsychotic medication with mMR = 1.75 95% CI: 1.41–2.16). Similarly, ethnicity and stage of disease didn''t affect results. Although S100B could be regarded as a possible biomarker of schizophrenia, limitations should be accounted when interpreting results, especially because of the high heterogeneity that remained >70%, even after carrying out subgroups analyses. These results point out that approaches based on traditional categorical diagnoses may be too restrictive and new approaches based on the characterization of new complex phenotypes should be considered.     

Maternal Mortality in Taiwan: A Nationwide Data Linkage Study

Background

To examine the changes in the maternal mortality ratio (MMR) and causes of maternal death in Taiwan based on nationwide linked data sets.

Methods

We linked four population-based data sets (birth registration, birth notification, National Health Insurance inpatient claims, and cause of death mortality data) to identify maternal deaths for 2004–2011. Subsequently, we calculated the MMR (deaths per 100,000 live births) and the proportion of direct and indirect causes of maternal death by maternal age and year.

Findings

Based on the linked data sets, we identified 236 maternal death cases, of which only 102 were reported in officially published mortality data, with an underreporting rate of 57% [(236−102) × 100 / 236]. The age-adjusted MMR was 18.4 in 2004–2005 and decreased to 12.5 in 2008–2009; however, the MMR leveled off at 12.6 in 2010–2011. The MMR increased from 5.2 in 2008–2009 to 7.1 in 2010–2011 for patients aged 15–29 years. Women aged 15–29 years had relatively lower proportion in dying from direct causes (amniotic fluid embolism and obstetric hemorrhage) compared with their counterpart older women.

Conclusions

Approximately two-thirds of maternal deaths were not reported in officially published mortality data. Routine surveillance of maternal mortality by using enhanced methods is necessary to monitor the health status of reproductive-age women. Furthermore, a comprehensive maternal death review is necessary to explore the preventability of these maternal deaths.     

LDx: Estimation of Linkage Disequilibrium from High-Throughput Pooled Resequencing Data

High-throughput pooled resequencing offers significant potential for whole genome population sequencing. However, its main drawback is the loss of haplotype information. In order to regain some of this information, we present LDx, a computational tool for estimating linkage disequilibrium (LD) from pooled resequencing data. LDx uses an approximate maximum likelihood approach to estimate LD (r²) between pairs of SNPs that can be observed within and among single reads. LDx also reports r² estimates derived solely from observed genotype counts. We demonstrate that the LDx estimates are highly correlated with r² estimated from individually resequenced strains. We discuss the performance of LDx using more stringent quality conditions and infer via simulation the degree to which performance can improve based on read depth. Finally we demonstrate two possible uses of LDx with real and simulated pooled resequencing data. First, we use LDx to infer genomewide patterns of decay of LD with physical distance in D. melanogaster population resequencing data. Second, we demonstrate that r² estimates from LDx are capable of distinguishing alternative demographic models representing plausible demographic histories of D. melanogaster.     

NIMH Project Accept (HPTN 043): Results from In-Depth Interviews with a Longitudinal Cohort of Community Members

Introduction

NIMH Project Accept (HPTN 043) is a community- randomized trial to test the safety and efficacy of a community-level intervention designed to increase testing and lower HIV incidence in Tanzania, Zimbabwe, South Africa and Thailand. The evaluation design included a longitudinal study with community members to assess attitudinal and behavioral changes in study outcomes including HIV testing norms, HIV-related discussions, and HIV-related stigma.

Methods

A cohort of 657 individuals across all sites was selected to participate in a qualitative study that involved 4 interviews during the study period. Baseline and 30-month data were summarized according to each outcome, and a qualitative assessment of changes was made at the community level over time.

Results

Members from intervention communities described fewer barriers and greater motivation for testing than those from comparison communities. HIV-related discussions in intervention communities were more grounded in personal testing experiences. A change in HIV-related stigma over time was most pronounced in Tanzania and Zimbabwe. Participants in the intervention communities from these two sites attributed community-level changes in attitudes to project specific activities.

Discussion

The Project Accept intervention was associated with more favorable social norms regarding HIV testing, more personal content in HIV discussions in all study sites, and qualitative changes in HIV-related stigma in two of five sites.