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To tackle the phenotypic heterogeneity of schizophrenia, data-driven methods are often applied to identify subtypes of its symptoms and cognitive deficits. However, a systematic review on this topic is lacking. The objective of this review was to summarize the evidence obtained from longitudinal and cross-sectional data-driven studies in positive and negative symptoms and cognitive deficits in patients with schizophrenia spectrum disorders, their unaffected siblings and healthy controls or individuals from general population. Additionally, we aimed to highlight methodological gaps across studies and point out future directions to optimize the translatability of evidence from data-driven studies. A systematic review was performed through searching PsycINFO, PubMed, PsycTESTS, PsycARTICLES, SCOPUS, EMBASE and Web of Science electronic databases. Both longitudinal and cross-sectional studies published from 2008 to 2019, which reported at least two statistically derived clusters or trajectories were included. Two reviewers independently screened and extracted the data. In this review, 53 studies (19 longitudinal and 34 cross-sectional) that conducted among 17,822 patients, 8729 unaffected siblings and 5520 controls or general population were included. Most longitudinal studies found four trajectories that characterized by stability, progressive deterioration, relapsing and progressive amelioration of symptoms and cognitive function. Cross-sectional studies commonly identified three clusters with low, intermediate (mixed) and high psychotic symptoms and cognitive profiles. Moreover, identified subgroups were predicted by numerous genetic, sociodemographic and clinical factors. Our findings indicate that schizophrenia symptoms and cognitive deficits are heterogeneous, although methodological limitations across studies are observed. Identified clusters and trajectories along with their predictors may be used to base the implementation of personalized treatment and develop a risk prediction model for high-risk individuals with prodromal symptoms.

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.

In general, smoking increases the risk of mortality. However, it is less clear how the relative risk varies by cause of death. The exact impact of changes in smoking habits throughout life on different mortality risks is less studied. We studied the impact of baseline and lifetime smoking habits, and duration of smoking on the risk of all-cause mortality, mortality of cardiovascular diseases (CVD), chronic obstructive pulmonary disease (COPD), any cancer and of the four most common types of cancer (lung, colorectal, prostate, and breast cancer) in a cohort study (Vlagtwedde-Vlaardingen 1965-1990, with a follow-up on mortality status until 2009, n = 8,645). We used Cox regression models adjusted for age, BMI, sex, and place of residence. Since previous studies suggested a potential effect modification of sex, we additionally stratified by sex and tested for interactions. In addition, to determine which cause of death carried the highest risk we performed competing-risk analyses on mortality due to CVD, cancer, COPD and other causes. Current smoking (light, moderate, and heavy cigarette smoking) and lifetime persistent smoking were associated with an increased risk of all-cause, CVD, COPD, any cancer, and lung cancer mortality. Higher numbers of pack years at baseline were associated with an increased risk of all-cause, CVD, COPD, any cancer, lung, colorectal, and prostate cancer mortality. Males who were lifetime persistent pipe/cigar smokers had a higher risk of lung cancer [HR (95% CI) = 7.72 (1.72-34.75)] as well as all-cause and any cancer mortality. A longer duration of smoking was associated with a higher risk of COPD, any and lung cancer [HR (95% CI) = 1.06 (1.00-1.12), 1.03 (1.00-1.06) and 1.10 (1.03-1.17) respectively], but not with other mortality causes. The competing risk analyses showed that ex- and current smokers had a higher risk of cancer, CVD, and COPD mortality compared to all other mortality causes. In addition, heavy smokers had a higher risk for COPD mortality compared to cancer, and CVD mortality. Our study indicates that lifetime numbers of cigarettes smoked and the duration of smoking have different impacts for different causes of mortality. Moreover, our findings emphasize the importance of smoking-related competing risks when studying the smoking-related cancer mortality in a general population and that smoking cessation immediately effectively reduces the risk of all-cause and any cancer mortality.

Background Genetic and environmental factors play a role in the development of COPD. The epigenome, and more specifically DNA methylation, is recognized as important link between these factors. We postulate that DNA methylation is one of the routes by which cigarette smoke influences the development of COPD. In this study, we aim to identify CpG-sites that are associated with cigarette smoke exposure and lung function levels in whole blood and validate these CpG-sites in lung tissue. Methods The association between pack years and DNA methylation was studied genome-wide in 658 current smokers with >5 pack years using robust linear regression analysis. Using mediation analysis, we subsequently selected the CpG-sites that were also associated with lung function levels. Significant CpG-sites were validated in lung tissue with pyrosequencing and expression quantitative trait methylation (eQTM) analysis was performed to investigate the association between DNA methylation and gene expression. Results 15 CpG-sites were significantly associated with pack years and 10 of these were additionally associated with lung function levels. We validated 5 CpG-sites in lung tissue and found several associations between DNA methylation and gene expression. Conclusion This study is the first to validate a panel of CpG-sites that are associated with cigarette smoking and lung function levels in whole blood in the tissue of interest: lung tissue.

Pre-eclampsia shares pathophysiology with intrauterine growth restriction. To investigate whether delivery of a small for gestational age (SGA) infant in the 1st pregnancy increases the risk of early and late onset pre-eclampsia in the 2nd pregnancy. Conversely, we investigated whether pre-eclampsia in the 1st pregnancy impacts SGA risk in the 2nd pregnancy. We studied a cohort from the Dutch Perinatal Registry of 265,031 women with 1st and 2nd singleton pregnancies who delivered between 2000 and 2007. We analyzed 2nd pregnancy risks of early and late onset pre-eclampsia-defined by delivery before or after 34 gestational weeks-as well as SGA below the 5th and between the 5th and 10th percentiles risks with multivariable logistic regressions. Interaction terms between 1st pregnancy hypertension, pre-eclampsia, SGA, and delivery before or after 34 gestational weeks were included in the regressions. First pregnancy early onset pre-eclampsia increased risk of SGA <5th percentile (OR 2.1, 95% CI 1.7-2.7) in the 2nd pregnancy. Late onset pre-eclampsia increased the SGA <5th percentile marginally (OR 1.1, 95% CI 1.0-1.3). In the absence of 1st pregnancy hypertensive disorder, women who delivered an SGA infant in their 1st pregnancy were at increased risk of 2nd pregnancy late onset pre-eclampsia (SGA <5th: OR 2.05, 95% CI 1.58-2.66; SGA 5-10th: OR 1.39, 95% CI 1.01-1.93). Early onset 2nd pregnancy pre-eclampsia risk was also increased, but this was only statistically significant for women who delivered an SGA infant below the 5th percentile in the 1st pregnancy (SGA <5th: OR 2.44, 95% CI 1.19-5.00; SGA 5-10th: OR 1.69, 95% CI 0.68-4.24;). Women with 1st pregnancy early onset pre-eclampsia have increased risk of SGA <5th percentile in the 2nd pregnancy. SGA in the 1st pregnancy increases pre-eclampsia risk in the 2nd pregnancy even in the absence of hypertensive disorders in the 1st pregnancy, although absolute risks remain low. These findings strengthen the evidence base associating intrauterine growth restriction with early onset pre-eclampsia.

In low-income countries, where socioeconomic adversities and perinatal distress are common, adverse birth outcomes are significant public health problems. In these settings, perinatal distress, i.e., high symptoms of anxiety, depression, and/or stress during pregnancy, may be linked with adverse birth outcomes. However, few prospective studies have investigated the impact of perinatal distress on adverse birth outcomes such as preterm birth (gestational age <37 weeks), low birth weight (<2.5 kg), and small for gestational age birth (birth weight below the 10th percentile for gestational age and sex). Our main objective was to assess the influence of perinatal distress on adverse birth outcomes. Secondly, to investigate if perinatal distress is an independent risk factor or a mediator in the pathway between socioeconomic adversity and adverse birth outcomes. In a prospective cohort study following 991 women from before 20 weeks of gestation until delivery in northern Ethiopia, we collected self-reported data on distress at a mean of 14.8 (standard deviation [SD] = 1.9) and 33.9 (SD = 1.1) weeks of gestation. Distress was measured using the Edinburgh Postnatal Depression Scale, the anxiety subscale of the Hospital Anxiety and Depression Scale, and the Perceived Stress Scale. To determine birth outcomes, gestational age was estimated from the last menstrual period, fundal palpation, and/or ultrasound, while birth weight was obtained from delivery records and measured within three days after birth for those delivered at home. Logistic regression and mediation analysis were employed to evaluate the impact of perinatal distress on adverse birth outcomes. Perinatal anxiety (OR [95% CI] 1.08 [1.02, 1.13]), depression (1.07 [1.03, 1.11]), stress (1.14 [1.07, 1.22]), and total distress (1.15 [1.07, 1.23]) were all associated with low birth weight, and small for gestational age birth but none did with preterm birth. Mediation analysis demonstrated that perinatal distress was a mediator in the pathway between socioeconomic adversity and adverse birth outcomes. Our study revealed that perinatal distress was linked with adverse birth outcomes and acted as a mediator between socioeconomic adversity and these outcomes. Our findings highlight the importance of screening women for distress and providing appropriate interventions, focusing on women experiencing socioeconomic adversity. Integrating mental health services into primary maternal care in low-income countries could be an effective approach to achieve this.

Abstract Asthma and chronic obstructive pulmonary disease (COPD) show similarities and substantial differences. The Dutch hypothesis stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the timing and type of environmental exposures (Postma and Boezen, Chest 2004;126:96S−104S). Thus, a particular group of shared genetic factors may lead to asthma when combined with specific environmental factors that are met at a certain stage in life, whereas combination with other environmental factors, or similar environmental factors at a different stage in life, will lead toward COPD. Multiple genes have been found for asthma and COPD. In addition to genes unique to these diseases, some shared genetic risk factors exist. Moreover, there are both common host risk factors and environmental risk factors for asthma and COPD. Here we put forward, based on the data available, that genes that affect lung development in utero and lung growth in early childhood in interaction with environmental detrimental stimuli, such as smoking and air pollution, are contributing to asthma in childhood and the ultimate development of COPD. Additional genes and environmental factors then drive specific immunological mechanisms underlying asthma, and others may contribute to the ultimate development of specific subtypes of COPD (i.e., airway disease with mucous hypersecretion, small airway disease, and emphysema). The genetic predisposition to the derailment of certain pathways may further help to define subgroups of asthma and COPD. In the end this may lead to stratification of patients by their genetic make-up and open new therapeutic prospects.

Chronic obstructive pulmonary disease (COPD) is a complex disorder with high mortality worldwide. Studies on the role of candidate genes and their polymorphisms in COPD development have so far produced ambiguous results. The aim of this study was to reveal the role of COPD candidate genes using data collected in previous research. We performed meta-analyses on 20 polymorphisms in 12 genes, after searching the PubMed and Embase databases for publications on COPD. These genes involve three main pathways associated with COPD development: the inflammatory, protease-antiprotease balance, and antioxidant pathways. We obtained significant results for three TGFB1 polymorphisms, although these were based only on a few studies. The IL1RN VNTR polymorphism increases the risk for COPD (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.09-2.65), whereas the TNFA -308 G/A polymorphism does so only in Asian populations (OR, 2.01; 95% CI, 1.21-3.31). The GSTP1 I105V polymorphism was protective for COPD in Asian populations only (OR, 0.69; 95% CI, 0.56-0.85). These results demonstrate the importance of ethnicity in identifying specific COPD genes.

Background A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. Methods We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (N case  = 12,550, N control  = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) ( N  = 458,969), high blood pressure (HBP) (N case  = 144,793, N control  = 313,761), coronary artery disease (CAD)(N case  = 60,801, N control  = 123,504), and stroke (N case  = 40,585, N control  = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. Results RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P  = 0.008). Conclusion In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.

The adverse effects of electronic waste (e-waste) on the human body have stirred up concern in recent years. China is one of the countries that confront serious pollution and human exposure of e-waste, and the majority of the population is exposed to potentially hazardous substances that are derived from informal e-waste recycling processes. This study reviews recent reports on human exposure to e-waste in China, with particular focus on exposure routes (e.g., inhalation and ingestion) and several toxicities of human (e.g., endocrine system, respiratory system, reproductive system, developmental toxicity, neurotoxicity, and genetic toxicity). Pieces of evidence that associate e-waste exposure with human health effects in China are assessed. The role of toxic heavy metals (e.g., lead, cadmium, chromium, mercury, and nickel) and organic pollutants (e.g., polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyl (PCBs), polycyclic aromatic hydrocarbons (PAHs), polybrominated biphenyls (PBBs), polyhalogenated aromatic hydrocarbons (PHAHs), bisphenol A (BPA)) on human health is also briefly discussed.