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The impact of baseline hypertension status on the BMI–mortality association is still unclear. We aimed to examine the moderation effect of hypertension on the BMI–mortality association using a rural Chinese cohort.
Design:
In this cohort study, we investigated the incident of mortality according to different BMI categories by hypertension status.
Setting:
Longitudinal population-based cohort
Participants:
17,262 adults ≥18 years were recruited from July to August of 2013 and July to August of 2014 from a rural area in China.
Results:
During a median 6-year follow-up, we recorded 1109 deaths (610 with and 499 without hypertension). In adjusted models, as compared with BMI 22-24 kg/m2, with BMI ≤18, 18-20, 20-22, 24-26, 26-28, 28-30 and >30 kg/m2, the HRs (95% CI) for mortality in normotensive participants were 1.92 (1.23-3.00), 1.44 (1.01-2.05), 1.14 (0.82-1.58), 0.96 (0.70-1.31), 0.96 (0.65-1.43), 1.32 (0.81-2.14), and 1.32 (0.74-2.35) respectively, and in hypertensive participants were 1.85 (1.08-3.17), 1.67 (1.17-2.39), 1.29 (0.95-1.75), 1.20 (0.91-1.58), 1.10 (0.83-1.46), 1.10 (0.80-1.52), and 0.61 (0.40-0.94) respectively. The risk of mortality was lower in individuals with hypertension with overweight or obesity versus normal weight, especially in older hypertensives (≥60 years old). Sensitivity analyses gave consistent results for both normotensive and hypertensive participants.
Conclusions:
Low BMI was significantly associated with increased risk of all-cause mortality regardless of hypertension status in rural Chinese adults, but high BMI decreased the mortality risk among individuals with hypertension, especially in older hypertensives.
Over recent decades, Chinese giant salamanders Andrias spp. have declined dramatically across much of their range. Overexploitation and habitat degradation have been widely cited as the cause of these declines. To investigate the relative contribution of each of these factors in driving the declines, we carried out standardized ecological and questionnaire surveys at 98 sites across the range of giant salamanders in China. We did not find any statistically significant differences between water parameters (temperature, dissolved oxygen, ammonia, nitrite, nitrate, salinity, alkalinity, hardness and flow rate) recorded at sites where giant salamanders were detected by survey teams and/or had been recently seen by local respondents, and sites where they were not detected and/or from which they had recently been extirpated. Additionally, we found direct and indirect evidence that the extraction of giant salamanders from the wild is ongoing, including within protected areas. Our results support the hypothesis that the decline of giant salamanders across China has been primarily driven by overexploitation. Data on water parameters may be informative for the establishment of conservation breeding programmes, an initiative recommended for the conservation of these species.
To understand the characteristics and influencing factors related to cluster infections in Jiangsu Province, China, we investigated case reports to explore transmission dynamics and influencing factors of scales of cluster infection. The effectiveness of interventions was assessed by changes in the time-dependent reproductive number (Rt). From 25th January to 29th February, Jiangsu Province reported a total of 134 clusters involving 617 cases. Household clusters accounted for 79.85% of the total. The time interval from onset to report of index cases was 8 days, which was longer than that of secondary cases (4 days) (χ2 = 22.763, P < 0.001) and had a relationship with the number of secondary cases (the correlation coefficient (r) = 0.193, P = 0.040). The average interval from onset to report was different between family cluster cases (4 days) and community cluster cases (7 days) (χ2 = 28.072, P < 0.001). The average time interval from onset to isolation of patients with secondary infection (5 days) was longer than that of patients without secondary infection (3 days) (F = 9.761, P = 0.002). Asymptomatic patients and non-familial clusters had impacts on the size of the clusters. The average reduction in the Rt value in family clusters (26.00%, 0.26 ± 0.22) was lower than that in other clusters (37.00%, 0.37 ± 0.26) (F = 4.400, P = 0.039). Early detection of asymptomatic patients and early reports of non-family clusters can effectively weaken cluster infections.
The East Asian winter monsoon (EAWM) is one of the most dynamic components of the global climate system. Although poorly understood, knowledge of long-term spatial differences in EAWM variability during the glacial–interglacial cycles is important for understanding the dynamic processes of the EAWM. We reconstructed the spatiotemporal characteristics of the EAWM since the last glacial maximum (LGM) using a comparison of proxy records and long-term transient simulations. A loess grain-size record from northern China (a sensitive EAWM proxy) and the sea surface temperature gradient of an EAWM index in sediments of the southern South China Sea were compared. The data–model comparison indicates pronounced spatial differences in EAWM evolution, with a weakened EAWM since the LGM in northern China but a strengthened EAWM from the LGM to the early Holocene, followed by a weakening trend, in southern China. The model results suggest that variations in the EAWM in northern China were driven mainly by changes in atmospheric carbon dioxide (CO2) concentration and Northern Hemisphere ice sheets, whereas orbital insolation and ice sheets were important drivers in southern China. We propose that the relative importance of insolation, ice sheets, and atmospheric CO2 for EAWM evolution varied spatially within East Asia.
Carotenoids are increasingly being implicated to have an important role in brain and eye development. This study aimed to quantify the content and profile of carotenoids in human breast milk, maternal plasma and neonatal umbilical cord plasma in Chengdu, an urban area in Southwest China. In this study, fifty-four healthy mothers were enrolled. Maternal blood, umbilical cord blood, colostrum, transitional milk and mature milk were collected. Concentrations of carotenoids (lutein, zeaxanthin, β-cryptoxanthin, β-carotene and lycopene) were analysed by HPLC. We found that carotenoid concentrations decreased from colostrum to mature milk. Hydrocarbon carotenoids with weaker polarity decreased more than the polar carotenoids. Lycopene concentrations dropped by 99 %, β-carotene by 92 %, β-cryptoxanthin by 83 %, lutein by 32 % and zeaxanthin by 22 %. Lycopene and β-carotene accounted for 70 % of the total carotenoids in colostrum, and lutein predominated amongst carotenoids in transitional milk and mature milk (51–55 %). Carotenoid concentrations in maternal plasma were much higher than that in cord plasma. Lutein predominated in cord plasma. The concentrations of all carotenoids in maternal plasma were correlated with those of cord plasma and human milk. These results are consistent with selective transport mechanisms in the mammary gland related to the polarity of carotenoids, and each carotenoid has its own implications, which may have different priorities in the early life development of infants. These findings may help guide dietary recommendations for carotenoid inclusion in infant formulas.
Narrowband microwave generation with tuneable frequency is demonstrated by illuminating a photoconductive semiconductor switch (PCSS) with a burst-mode fibre laser. The whole system is composed of a high-power linearly polarized burst-mode pulsed fibre laser and a linear-state PCSS. To obtain a high-performance microwave signal, a desired envelope of burst is necessary and a pulse pre-compensation technique is adopted to avoid envelope distortion induced by the gain-saturation effect. Resulting from the technique, homogenous peak power distribution in each burst is ensured. The maximum energy of the laser burst pulse reaches 200 μJ with a burst duration of 100 ns at the average power of 10 W, corresponding to a peak power of 4 kW. When the PCSS is illuminated by the burst-mode fibre laser, narrowband microwave generation with tuneable frequency (0.80–1.12 GHz) is obtained with a power up to 300 W. To the best of the authors’ knowledge, it is the first demonstration of frequency-tuneable narrowband microwave generation based on a fibre laser. The high-power burst-mode fibre laser reported here has great potential for generating high-power arbitrary microwave signals for a great deal of applicable demands such as smart adaptive radar and intelligent high-power microwave systems.
Clinical atherosclerotic cardiovascular disease (ASCVD) patients are judged to be very-high-risk if they had a history of multiple major ASCVD events, or one major ASCVD event with multiple high-risk conditions. Very-high-risk ASCVD patients are under high risk of adverse clinical events and need more attention in the management of secondary prevention. This real-world study aimed at estimating the prevalence of very-high-risk ASCVD and investigating the occurrence of adverse clinical events and associated risk factors among patients with very-high-risk ASCVD in China.
Methods
Data were obtained from the Urban Employee Basic Medical Insurance database in Tianjin, China. Very-high-risk ASCVD patients were identified from 2014 to 2015 through the history of ASCVD events and evidence of high-risk conditions, and followed for 24 months. Adverse clinical events were measured by major adverse cardiovascular events (MACE), a composite endpoint of stroke, myocardial infarction (MI) and death. A Cox regression model was used to identify risk factors of MACE, adjusting for potential confounders.
Results
The percentage of clinical ASCVD patients identified as very-high-risk was 35.2 (N = 41,181), while 34,740 patients with continuous enrollment were included (mean age: 67.1 years; 42.5% female). The percentage of patients who had MACE in the 24-month follow-up period was 27.7, with stroke (22.3%) as the most prevalent event followed by death (6.9%) and MI (1.3%). Male gender, older age, and having MI or ischemic stroke (versus unstable angina) as the index major ASCVD event were risk predictors of MACE.
Conclusions
More than one-third of patients with clinical ASCVD are under very-high-risk in China, and among them 27.7 percent experience MACE during a 24-month follow-up period. Male patients, older patients, and patients who had MI or ischemic stroke are under higher risk of experiencing MACE. Future studies are warranted for comparing the differences in characteristics, pattern of drug use, occurrence of adverse clinical events and medical burden between very-high-risk ASCVD patients and ASCVD patients not at very-high-risk.
Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
The present study aimed to investigate the association of the Chinese visceral adiposity index (CVAI) and its 6-year change with hypertension risk and compare the ability of CVAI and other obesity indices to predict hypertension based on the Rural Chinese Cohort Study. Study participants were randomly recruited by a cluster sampling procedure, and 10 304 participants ≥18 years were included. Modified Poisson regression was used to derive adjusted relative risks (RR) and 95 % CI. We identified 2072 hypertension cases during a median of 6·03 years of follow-up. The RR for the highest v. lowest CVAI quartile were 1·29 (95 % CI 1·05, 1·59) for men and 1·53 (95 % CI 1·22, 1·91) for women. Per-sd increase in CVAI was associated with hypertension for both men (RR 1·09, 95 % CI 1·02, 1·16) and women (RR 1·14, 95 % CI 1·06, 1·22). Also, the area under the receiver operating characteristic curve value for hypertension was higher for CVAI than the four other obesity indices for both sexes (all P < 0·05). Finally, per-sd increase in CVAI change was associated with hypertension for both men (RR 1·26, 95 % CI 1·16, 1·36) and women (RR 1·23, 95 % CI 1·15, 1·30). Similar results were observed in sensitivity analyses. CVAI and its 6-year change are positively associated with hypertension risk. CVAI has better performance in predicting hypertension than other visceral obesity indices for both sexes. The current findings suggest CVAI as a reliable and applicable predictor of hypertension in rural Chinese adults.
To evaluate the dynamic properties of a coupled structure based on the dynamic properties of its substructures, this paper investigates the dynamic substructuring issue from the perspective of response prediction. The main idea is that the connecting forces at the interface of substructures can be expressed by the unknown coupled structural responses, and the responses can be solved rather easily. Not only rigidly coupled structures but also resiliently coupled structures are investigated. In order to further comprehend and visualize the nature of coupling problems, the Neumann series expansion for a matrix describing the relation between the coupled and uncoupled substructures is also introduced in this paper. Compared with existing response prediction methods, the proposed method does not have to measure any forces, which makes it easier to apply than the others. Clearly, the frequency response function matrix of coupled structures can be derived directly based on the response prediction method. Compared with existing frequency response function synthesis methods, it is more straightforward and comprehensible. Through demonstration of two examples, it is concluded that the proposed method can deal with structural coupling problems very well.
Understanding the patterns of treatment response is critical for the treatment of patients with schizophrenia; one way to achieve this is through using a longitudinal dynamic process study design.
Aims
This study aims to explore the response trajectory of antipsychotics and compare the treatment responses of seven different antipsychotics over 6 weeks in patients with schizoprenia (trial registration: Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934).
Method
Data were collected from a multicentre, randomised open-label clinical trial. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) at baseline and follow-up at weeks 2, 4 and 6. Trajectory groups were classified by the method of k-means cluster modelling for longitudinal data. Trajectory analyses were also employed for the seven antipsychotic groups.
Results
The early treatment response trajectories were classified into a high-trajectory group of better responders and a low-trajectory group of worse responders. The results of trajectory analysis showed differences compared with the classification method characterised by a 50% reduction in PANSS scores at week 6. A total of 349 patients were inconsistently grouped by the two methods, with a significant difference in the composition ratio of treatment response groups using these two methods (χ2 = 43.37, P < 0.001). There was no differential contribution of high- and low trajectories to different drugs (χ2 = 12.52, P = 0.051); olanzapine and risperidone, which had a larger proportion in the >50% reduction at week 6, performed better than aripiprazole, quetiapine, ziprasidone and perphenazine.
Conclusions
The trajectory analysis of treatment response to schizophrenia revealed two distinct trajectories. Comparing the treatment responses to different antipsychotics through longitudinal analysis may offer a new perspective for evaluating antipsychotics.
Lead-free ferroelectric electrocaloric ceramics that could convert electrical energy into heat are the promising candidate for environment-friendly cooling devices. For refrigeration devices, a large temperature change (ΔT) and good temperature stability are required, which are highly related to the phase structure and the applied electric field. In this work, a diffused ferroelectric–paraelectric (FP) phase transition is formed in (K, Na)NbO3 (KNN) by using appropriate composition engineering. The relaxor ferroelectrics in this work present both a large ΔT of 1.24 K and a high ΔT/ΔE of 0.19 K mm/kV. In addition, a wide temperature span exceeds 55 °C at the high electrocaloric effect (ECE) criterion (ΔT ≥ 0.5 K) could also be observed. This work not only opens a new strategy for obtaining high-performance ceramics for refrigeration devices but also extends the application area of the KNN-based lead-free ferroelectrics from sensors, actuators and energy harvesting to solid-state cooling applications.
Chronic fatigue syndrome (CFS) is characterized by extreme fatigue and disabling symptoms. Women with CFS often have a high risk of gynaecological problems such as irregular menstruation, endometriosis and pelvic pain and sexual dysfunction. Our previous results have shown that, in pregnant mice, CFS significantly decreased the progestational hormone level in serum, as well as learning and memory, and the function of the hypothalamus–pituitary–gonadal axis. In addition, the F1 generation also suffered from congenital hypothyroidism. At present, there has been no report about placenta formation and embryonic development in pregnant mice with CFS. The aim of the present study was to investigate the influence of CFS on the morphology, oxidative stress and Wnt/β-catenin signalling pathway during placenta formation. In this study, we found that CFS decreased the number of implantation sites for blastocysts, and increased the number of absorbed, stillborn and malformed fetuses. The morphology and structure of the placenta were abnormal in pregnant mice with CFS. Further study found that the oxidative stress in serum, uterus and placenta was increased in pregnant mice with CFS, while the levels of antioxidase were decreased. CFS also inhibited the Wnt/β-catenin signalling pathway in the placenta. These results suggested that inhibition of the Wnt/β-catenin signalling pathway and enhanced oxidative stress play an important role in abnormal placentation in pregnant mice with CFS.
There is growing interest globally in using real-world data (RWD) and real-world evidence (RWE) for health technology assessment (HTA). Optimal collection, analysis, and use of RWD/RWE to inform HTA requires a conceptual framework to standardize processes and ensure consistency. However, such framework is currently lacking in Asia, a region that is likely to benefit from RWD/RWE for at least two reasons. First, there is often limited Asian representation in clinical trials unless specifically conducted in Asian populations, and RWD may help to fill the evidence gap. Second, in a few Asian health systems, reimbursement decisions are not made at market entry; thus, allowing RWD/RWE to be collected to give more certainty about the effectiveness of technologies in the local setting and inform their appropriate use. Furthermore, an alignment of RWD/RWE policies across Asia would equip decision makers with context-relevant evidence, and improve timely patient access to new technologies. Using data collected from eleven health systems in Asia, this paper provides a review of the current landscape of RWD/RWE in Asia to inform HTA and explores a way forward to align policies within the region. This paper concludes with a proposal to establish an international collaboration among academics and HTA agencies in the region: the REAL World Data In ASia for HEalth Technology Assessment in Reimbursement (REALISE) working group, which seeks to develop a non-binding guidance document on the use of RWD/RWE to inform HTA for decision making in Asia.
This cross-sectional study aimed to examine the associations between dietary fibre (DF) intake and depressive symptoms in a general adult population in Tianjin, China. A total of 24 306 participants (mean age 41 years; range 18–91 years) were enrolled. DF intake was assessed using a validated self-administered FFQ. Depressive symptoms were assessed using the Self-Rating Depression Scale. Associations between DF intake and depressive symptoms were estimated using logistic regression analysis. Socio-demographic, behavioural, health status and dietary factors were adjusted. In men, compared with participants in the lowest quartiles for total, soluble, vegetable and soya DF, OR for depressive symptoms in the highest were 0·83 (95 % CI 0·69, 0·99), 0·74 (95 % CI 0·63, 0·87), 0·79 (95 % CI 0·65, 0·96) and 0·69 (95 % CI 0·60, 0·81), respectively. In women, compared with participants in the lowest quartiles for vegetable and soya DF, the OR for depressive symptoms in the highest were 0·77 (95 % CI 0·64, 0·93) and 0·82 (95 % CI 0·70, 0·95), respectively. No association was found between total or soluble DF intake and depressive symptoms in women. No association was found between insoluble, cereal, fruit or tuber DF intake and depressive symptoms in men and women. Linear associations between DF intake and depressive symptoms were only detected for soya DF (men, β = –0·148, P < 0·0001; women, β = –0·069, P = 0·04). Results suggest that intake of soluble, vegetable and soya DF was inversely associated with depressive symptoms. These results should be confirmed through prospective and interventional studies.
Fullerene dimers have attracted extensive attention due to their unique structures and fascinating properties. Here, fullerene dimer derivatives with four to six carbon atoms in the esters are designed and synthesized. The property differences that caused by the carbon number in the esters of the fullerene dimers are investigated by performing their electrochemical, optical, and photoelectric measurements. As the carbon atom numbers in the esters increase from four to five and six, the absorption intensities increase to 1.6- and 4.4-folds. The intensities of the fluorescence spectra increase to 1.8- and 5.2-folds. Their photocurrent increases to 2- and 7-folds under the irradiation of a 405-nm laser. The LUMO energy levels move downward slightly from −3.89 to −3.90 and −3.92 eV, respectively. Our results indicate that as the carbon number increases, the carbon chain lengths in the ester structures increase, very slight effects produced on the energy levels of the fullerene dimers, but strongly contribute to their chemical activities and thus the photoelectronic efficiencies.
A one-dimensional steady-state model for stimulated Raman backscatter (SRS) and stimulated Brillouin backscatter (SBS) processes in laser-irradiated plasmas is presented. Based on a novel “predictor-corrector” method, the model is capable to deal with broadband scattered light and inhomogeneous plasmas, exhibiting robustness and high efficiency. Influences of the electron density and temperature on the linear gains of both SRS and SBS are investigated, which indicates that the SRS gain is more sensitive to the electron density and temperature than that of the SBS. For the low-density case, the SBS dominates the scattering process, while the SRS exhibits much higher reflectivity in the high-density case. The nonlinear saturation mechanisms and competition between SRS and SBS are included in our model by a phenomenological method. The typical anti-correlation between SRS and SBS versus electron density is reproduced in the model. Calculations of the reflectivities are qualitatively in agreement with the typical results of experiments and simulations.
Dysregulation in hepatic lipid synthesis by excess dietary carbohydrate intake is often relevant with the occurrence of fatty liver; therefore, the thorough understanding of the regulation of lipid deposition and metabolism seems crucial to search for potential regulatory targets. In the present study, we examined TAG accumulation, lipid metabolism-related gene expression, the enzyme activities of lipogenesis-related enzymes, the protein levels of transcription factors or genes involving lipogenesis in the livers of yellow catfish fed five dietary carbohydrate sources, such as glucose, maize starch, sucrose, potato starch and dextrin, respectively. Generally speaking, compared with other carbohydrate sources, dietary glucose promoted TAG accumulation, up-regulated lipogenic enzyme activities and gene expressions, and down-regulated mRNA expression of genes involved in lipolysis and small ubiquitin-related modifier (SUMO) modification pathways. Further studies found that sterol regulatory element binding protein 1 (SREBP1), a key transcriptional factor relevant to lipogenic regulation, was modified by SUMO1. Mutational analyses found two important sites for SUMOylation modification (K254R and K264R) in SREBP1. Mutant SREBP lacking lysine 264 up-regulated the transactivation capacity on an SREBP-responsive promoter. Glucose reduced the SUMOylation level of SREBP1 and promoted the protein expression of SREBP1 and its target gene stearoyl-CoA desaturase 1 (SCD1), indicating that SUMOylation of SREBP1 mediated glucose-induced hepatic lipid metabolism. Our study elucidated the molecular mechanism of dietary glucose increasing hepatic lipid deposition and found that the SREBP-dependent transactivation was regulated by SUMO1 modification, which served as a new target for the transcriptional programmes governing lipid metabolism.
The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT) to identify malnutrition risk in patients with liver disease. However, little is known about the application of the RFH-NPT to screen for the risk of malnutrition in China, where patients primarily suffer from hepatitis virus-related cirrhosis. A total of 155 cirrhosis patients without liver cancer or uncontrolled co-morbid illness were enrolled in this prospective study. We administered the Nutritional Risk Screening 2002 (NRS-2002), RFH-NPT, Malnutrition Universal Screening Tool (MUST) and Liver Disease Undernutrition Screening Tool (LDUST) to the patients within 24 h after admission and performed follow-up observations for 1·5 years. The RFH-NPT and NRS-2002 had higher sensitivities (64·8 and 52·4 %) and specificities (60 and 70 %) than the other tools with regard to screening for malnutrition risk in cirrhotic patients. The prevalence of nutritional risk was higher under the use of the RFH-NPT against the NRS-2002 (63 v. 51 %). The RFH-NPT tended more easily to detect malnutrition risk in patients with advanced Child–Pugh classes (B and C) and lower Model for End-stage Liver Disease scores (<15) compared with NRS-2002. RFH-NPT score was an independent predictive factor for mortality. Patients identified as being at high malnutrition risk with the RFH-NPT had a higher mortality rate than those at low risk; the same result was not obtained with the NRS-2002. Therefore, we suggest that using the RFH-NPT improves the ability of clinicians to predict malnutrition risk in patients with cirrhosis primarily caused by hepatitis virus infection at an earlier stage.
The link between schizophrenia and cigarette smoking has been well established through observational studies. However, the cause–effect relationship remains unclear.
Aims
We conducted Mendelian randomisation analyses to assess any causal relationship between genetic variants related to four smoking-related traits and the risk of schizophrenia.
Method
We performed a two-sample Mendelian randomisation using summary statistics from genome-wide association studies (GWAS) of smoking-related traits and schizophrenia (7711 cases, 18 327 controls) in East Asian populations. Single nucleotide polymorphisms (SNPs) correlated with smoking behaviours (smoking initiation, smoking cessation, age at smoking initiation and quantity of smoking) were investigated in relation to schizophrenia using the inverse-variance weighted (IVW) method. Further sensitivity analyses, including Mendelian randomisation-Egger (MR-Egger), weighted median estimates and leave-one-out analysis, were used to test the consistency of the results.
Results
The associated SNPs for the four smoking behaviours were not significantly associated with schizophrenia status. Pleiotropy did not inappropriately affect the results.
Conclusions
Cigarette smoking is a complex behaviour in people with schizophrenia. Understanding factors underlying the observed association remains important; however, our findings do not support a causal role of smoking in influencing risk of schizophrenia.