Associations of early retirement and mortality risk: a population-based study in Taiwan.

BACKGROUND: Early retirement is highly prevalent in Taiwan. This study assesses the association between early retirement and all-cause and cause-specific mortality risks while exploring the modifying effect of sociodemographic factors. METHODS: Using Taiwan's National Health Insurance Research Database between 2009 and 2019, 1 762 621 early retirees aged 45-64 and an equal number of employed comparators were included. The date and cause of death were identified using the National Death Registry. Cox regression models were used to estimate HRs of early retirement for all-cause mortality and cause-specific mortality. To explore modifying effects, we conducted subgroup analyses based on age groups, sexes, occupation types and general health status (Charlson Comorbid Index score). RESULTS: The analysis revealed that early retirees, compared with their concurrently employed counterparts, had a higher mortality risk (adjusted HR (aHR) 1.69, 95% CI (1.67 to 1.71)). Specifically, younger individuals (aged 45-54) (aHR 2.74 (95% CI 2.68 to 2.80)), males (aHR 1.78 (95% CI 1.76 to 1.81)), those in farming or fishing occupations (aHR 2.13 (95% CI 2.06 to 2.21)) or the private sector (aHR 1.92 (95% CI 1.89 to 1.96)), and those with the poorest health conditions (aHR 1.79 (95% CI 1.76 to 1.83)) had higher mortality risks of early retirement. Regarding specific causes of death, the top three highest risks were associated with gastrointestinal disorders, followed by suicide and neurological disorders. CONCLUSIONS: This study underscores the substantial mortality risk increase linked to early retirement, emphasising the importance of policy considerations, particularly regarding vulnerable populations and specific causes of death potentially linked to unhealthy lifestyles.

Widowhood and mortality risk in Taiwan: a population-based matched cohort study.

BACKGROUND: Studying the causes of death among deceased spouses and surviving partners may provide insights into the underlying mechanisms of the association between widowhood and mortality. This study investigated the mortality risk of widowhood in Taiwan, examined the association of the cause of death between widowed individuals and their deceased spouses and explored potential modifying effects by age, gender and duration after widowhood. METHODS: This matched cohort study utilized Taiwan's National Health Insurance claims database and National Death Registry. In total, 204 010 widowed men and 596 136 widowed women were identified with a mean follow-up period of 6.9 and 7.9 years, respectively, and 816 040 comparison men and 2 384 544 comparison women were selected. RESULTS: Widowhood was associated with an increased mortality risk, with widowed men having a 1.32 increased risk and widowed women having a 1.27 increased risk. Age at spousal death and duration modified the associations after widowhood. The widowed individuals are more likely to die by the same cause as the deceased spouse if they died by suicide, accident, endocrine, gastrointestinal disorders or infection. CONCLUSIONS: The study suggests that healthcare policies and interventions should be developed to improve widowed individuals' health and overall welfare.

Impact of the trans-ancestry polygenic risk score on type 2 diabetes risk, onset age and progression among population in Taiwan.

Type 2 diabetes (T2D) prevalence in adults at a younger age has increased but the disease status may go unnoticed. This study aimed to determine whether the onset age and subsequent diabetic complications can be attributed to the polygenic architecture of T2D in the Taiwan Han population. A total of 9,627 cases with T2D and 85,606 controls from the Taiwan Biobank were enrolled. Three diabetic polygenic risk scores (PRSs), PRS_EAS and PRS_EUR, and a trans-ancestry PRS (PRS_META), calculated using summary statistic from East Asian and European populations. The onset age was identified by linking to the National Taiwan Insurance Research Database, and the incidence of different diabetic complications during follow-up was recorded. PRS_META (7.4%) explained a higher variation for T2D status. And the higher percentile of PRS is also correlated with higher percentage of T2D family history and prediabetes status. More, the PRS was negatively associated with onset age (ß = -0.91 yr), and this was more evident among males (ß = -1.11 vs. -0.76 for males and females, respectively). The hazard ratio of diabetic retinopathy (DR) and diabetic foot were significantly associated with PRS_EAS and PRS_META, respectively. However, the PRS was not associated with other diabetic complications, including diabetic nephropathy, cardiovascular disease, and hypertension. Our findings indicated that diabetic PRS which combined susceptibility variants from cross-population could be used as a tool for early screening of T2D, especially for high-risk populations, such as individuals with high genetic risk, and may be associated with the risk of complications in subjects with T2D. NEW & NOTEWORTHY Our findings indicated that diabetic polygenic risk score (PRS) which combined susceptibility variants from Asian and European population affect the onset age of type 2 diabetes (T2D) and could be used as a tool for early screening of T2D, especially for individuals with high genetic risk, and may be associated with the risk of diabetic complications among people in Taiwan.

Suppressing the expression of glutathione S-transferase gene GSTd10 increases the sensitivity of Zeugodacus cucurbitae against ß-cypermethrin.

Zeugodacus cucurbitae Coquillett (Diptera: Tephritidae) is an agriculturally and economically important pest worldwide that has developed resistance to ß-cypermethrin. Glutathione S-transferases (GSTs) have been reported to be involved in the detoxification of insecticides in insects. We have found that both ZcGSTd6 and ZcGSTd10 were up-regulated by ß-cypermethrin induction in our previous study, so we aimed to explore their potential relationship with ß-cypermethrin tolerance in this study. The heterologous expression of ZcGSTd6 and ZcGSTd10 in Escherichia coli showed significantly high activities against 1-chloro-2,4-dinitrobenzene (CDNB). The kinetic parameters of ZcGSTd6 and ZcGSTd10 were determined by Lineweaver-Burk. The Vmax and Km of ZcGSTd6 were 0.50 µmol/min·mg and 0.3 mM, respectively. The Vmax and Km of ZcGSTd10 were 1.82 µmol/min·mg and 0.53 mM. The 3D modelling and molecular docking results revealed that ß-cypermethrin exhibited a stronger bounding to the active site SER-9 of ZcGSTd10. The sensitivity to ß-cypermethrin was significantly increased by 18.73% and 27.21%, respectively, after the knockdown of ZcGSTd6 and ZcGSTd10 by using RNA interference. In addition, the inhibition of CDNB at 50% (IC50) and the inhibition constants (Ki) of ß-cypermethrin against ZcGSTd10 were determined as 0.41 and 0.33 mM, respectively. The Ki and IC50 of ß-cypermethrin against ZcSGTd6 were not analysed. These results suggested that ZcGSTd10 could be an essential regulator involved in the tolerance of Z. cucurbitae to ß-cypermethrin.

Percutaneous Coronary Intervention With a Drug-Eluting Stent Versus Coronary Artery Bypass Grafting in Patients Receiving Dialysis: A National Study From Taiwan.

Rationale & Objective: We aimed to study the comparative effectiveness of percutaneous coronary intervention with drug-eluting stent and coronary artery bypass grafting in patients receiving dialysis. Study Design: This was a retrospective observational cohort study. Setting & Participants: This population-based study identified patients receiving dialysis hospitalized for coronary revascularization between January 1, 2009 and December 31, 2015, in the Taiwan National Health Insurance Research Database. Exposures: Patients received percutaneous coronary intervention with drug-eluting stent versus coronary artery bypass grafting. Outcomes: The study outcomes were all-cause mortality, in-hospital mortality, and repeat revascularization. Analytical Approach: Propensity scores were used to match patients. Cox proportional hazards models and logistic regression models were constructed to examine associations between revascularization strategies and mortality. Interval Cox models were fitted to estimate time-varying hazards during different periods. Results: A total of 1,840 propensity score-matched patients receiving dialysis were analyzed. Coronary artery bypass grafting was associated with higher in-hospital mortality (coronary artery bypass grafting vs percutaneous coronary intervention with drug-eluting stent; crude mortality rate 12.5% vs 3.3%; adjusted OR, 5.22; 95% CI, 3.42-7.97; P < 0.001) and longer hospitalization duration (median [IQR], 20 [14-30] days vs 3 [2-8] days; P < 0.001). After discharge, repeat revascularization, acute coronary syndrome, and repeat hospitalization all occurred more frequently in the percutaneous coronary intervention with drug-eluting stent group. Importantly, with a median follow-up of 2.8 years, coronary artery bypass grafting was significantly associated with a higher risk of all-cause overall mortality (adjusted HR, 1.19; 95% CI, 1.05-1.35; P = 0.006) in the multivariable Cox proportional hazard model. Sensitivity and subgroup analyses yielded consistent results. Limitations: This was an observational study with mainly Asian ethnicity. Conclusions: Percutaneous coronary intervention with drug-eluting stent may be associated with better survival than coronary artery bypass grafting in patients receiving dialysis. Future studies are warranted to confirm this finding.

Although coronary artery bypass grafting offers better long-term survival in the general population than percutaneous coronary intervention with drug-eluting stent, patients receiving dialysis may be too frail to tolerate the increased perioperative mortality risk of coronary artery bypass grafting. In this retrospective study in a national cohort of patients receiving dialysis from Taiwan, percutaneous coronary intervention with drug-eluting stent is associated with lower in-hospital mortality and better long-term survival when compared with coronary artery bypass grafting. Subsequent acute coronary syndrome, repeat revascularization, and rehospitalization were noted more frequently in the percutaneous coronary intervention with drug-eluting stent group. These findings may suggest percutaneous coronary intervention with drug-eluting stent as a safe revascularization strategy for patients receiving dialysis.

Familial factors rather than paternal age contribute to the aetiology of epilepsy.

BACKGROUND: Whether paternal age associated with offspring's epilepsy risk is a cause of de novo mutation as men age, or just an association due to confounding factors, is still unclear. METHODS: We performed a population-based, multi-generation and sibling comparison study in Taiwan, which included 2 751 232 singletons born in 2001-17 who were followed until 2020. Of these, 819 371/826 087 with information on paternal/maternal grandparents were selected for multi-generation analyses and 1 748 382 with sibling(s) were selected for sibling comparison. Cox proportional hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: In the total cohort, there was an increased risk of epilepsy in individuals with advanced paternal age, e.g. the HR for paternal age ≥50 was1.36 (95% CI: 1.15-1.61) compared with paternal age 25-29, and fathers older than mothers, e.g. the HR for parental age difference ≥15 years was 1.29 (95% CI: 1.16-1.43). When accounting for parental age difference, the association between paternal age and epilepsy in offspring was attenuated (HR for paternal age ≥50 was 1.11, 95% CI: 0.93-1.34). Multi-generation analyses did not support the association of advanced grand-paternal age at childbirth of the parent with offspring's risk of epilepsy. Sibling comparison analyses did not support the association of older paternal age with increased risk of epilepsy (HR was 0.96 for per year increase in paternal age, 95% CI: 0.96-0.97). CONCLUSIONS: These results do not support the hypothesis that advanced paternal age is associated with epilepsy in offspring. Instead, familial factors may explain the observed paternal age association with the offspring's risk of epilepsy.

Analysis across Taiwan Biobank, Biobank Japan, and UK Biobank identifies hundreds of novel loci for 36 quantitative traits.

Genome-wide association studies (GWASs) have identified tens of thousands of genetic loci associated with human complex traits. However, the majority of GWASs were conducted in individuals of European ancestries. Failure to capture global genetic diversity has limited genomic discovery and has impeded equitable delivery of genomic knowledge to diverse populations. Here we report findings from 102,900 individuals across 36 human quantitative traits in the Taiwan Biobank (TWB), a major biobank effort that broadens the population diversity of genetic studies in East Asia. We identified 968 novel genetic loci, pinpointed novel causal variants through statistical fine-mapping, compared the genetic architecture across TWB, Biobank Japan, and UK Biobank, and evaluated the utility of cross-phenotype, cross-population polygenic risk scores in disease risk prediction. These results demonstrated the potential to advance discovery through diversifying GWAS populations and provided insights into the common genetic basis of human complex traits in East Asia.

Association between 14 candidate genes, PM2.5, and affective disorders: a study of the Taiwan Biobank.

BACKGROUND: Most studies have focused on the risk factors, treatment, and care of affective psychosis, and several have reported a relationship between ambient air quality and this psychosis. Although an association has been reported between psychosis and genes, studies mainly explored the associations between one type of psychosis and one gene; few have identified genes related to affective psychosis. This study investigates the genetic and environmental factors of affective psychosis. METHODS: In this retrospective longitudinal study, 27 604 participants aged 30-70 were selected from Taiwan Biobank. The participants' propensity scores were calculated based on their demographic information, and propensity score matching was performed to divide the participants into an experimental (i.e., affective psychosis) and control group at a 1:5 ratio. Plink was used to analyze the major and minor types of gene expression related to affective psychosis, and PM2.5 exposure was incorporated into the analyses. RESULTS: According to the generalized estimating equation analysis results, 8 single nucleotide polymorphisms (SNPs) belonging to the ANK3, BDNF, CACNA1C, and GRID1 genotypes were significantly correlated with depressive disorder (P < .001), with the majority belonging to the ANK3 and CACNA1C. A total of 5 SNPs belonging to the CACNA1C, GRID1, and SIRT1 genotypes were significantly correlated with bipolar disorder (P < .001), with the majority belonging to the CACNA1C. No significant correlation was identified between ambient air pollution and affective psychosis. CONCLUSIONS: CACNA1C and GRID1 are common SNP genotypes for depressive disorder and bipolar disorder and should be considered associated with affective psychosis.

Adjunctive transcranial direct current stimulation (tDCS) plus sodium benzoate for the treatment of early-phase Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.

Previous studies found that an NMDA receptor (NMDAR) enhancer, sodium benzoate, improved cognitive function of patients with early-phase Alzheimer's disease (AD). Transcranial direct current stimulation (tDCS) induces NMDAR-dependent synaptic plasticity and strengthens cognitive function of AD patients. This study aimed to evaluate efficacy and safety of tDCS plus benzoate in early-phase dementia. In this 24-week randomized, double-blind, placebo-controlled trial, 97 patients with early-phase AD received 10-session tDCS during the first 2 weeks. They then took benzoate or placebo for 24 weeks. We assessed the patients using Alzheimer's disease assessment scale - cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change plus Caregiver Input, Mini Mental Status Examination, Alzheimer's disease Cooperative Study scale for ADL in MCI, and a battery of additional cognitive tests. Forty-seven patients received sodium benzoate, and the other 50 placebo. The two treatment groups didn't differ significantly in ADAS-cog or other measures. Addition of benzoate to tDCS didn't get extra benefit or side effect in this study. For more thoroughly studying the potential of combining tDCS with benzoate in the AD treatment, future research should use other study designs, such as longer-term benzoate treatment, adding benzoate in the middle of tDCS trial sessions, or administering benzoate then tDCS.

Association between neighborhood availability of physical activity facilities and cognitive performance in older adults.

The existing evidence on the contextual influence of the availability of local facilities for physical activity on the cognitive health of elderly residents is sparse. This study examined the association between neighborhood physical activity facilities and cognitive health in older individuals. A cohort study of community-dwelling older adults was performed using baseline data and follow-up data from the Taiwan Biobank. Cognitive health was measured in 32,396 individuals aged 60-70 years using the Mini-Mental State Examination (MMSE) with follow-up information on 8025 participants. The district was used as the proxy for local neighborhood. To determine neighborhood physical activity facilities, school campuses, parks, activity centers, gyms, swimming pools, and stadiums were included. Multilevel linear regression models were applied to examine the associations of neighborhood physical activity facilities with baseline MMSE and MMSE decline during follow-up, with adjustment for individual factors and neighborhood socioeconomic characteristics. Multilevel analyses revealed that there was a neighborhood-level effect on cognitive health among older adults. After adjusting for compositional and neighborhood socioeconomic characteristics, baseline MMSE was higher in individuals living in the middle- (beta = 0.12, p-value = 0.140) and high-density facility (beta = 0.22, p-value = 0.025) groups than in the low-density group (p-value for trend-test = 0.031). MMSE decline during follow-up was slower in the middle- (beta = 0.15, p-value = 0.114) and high-density facility (beta = 0.27, p-value = 0.052) groups than in the low-density group (p-value for trend-test = 0.032). Greater neighborhood availability of physical activity facilities was associated with better cognitive health among older residents. These findings have implications for designing communities and developing strategies to support cognitive health of an aging population.

Causal influence of sleeping phenotypes on the risk of coronary artery disease and sudden cardiac arrest: A Mendelian randomization analysis.

OBJECTIVES: To assess the causal influence of sleep and circadian traits on coronary artery disease and sudden cardiac arrest with adjustment for obesity through a two-sample Mendelian randomization study. METHODS: We used summary statistics of 5 sleep and circadian traits for genome-wide association studies, including chronotype, sleep duration, long sleep (≥9 h a day), short sleep (<7 h a day), and insomnia (sample size range: 237,622-651,295). Coronary artery disease genome-wide association studies with 60,801 cases and 123,504 controls, sudden cardiac arrest genome-wide association studies with 3939 cases and 25,989 controls, and obesity genome-wide association studies with 806,834 individuals were also used. Multivariable Mendelian randomization was performed to estimate the causality. RESULTS: After adjusting for obesity, genetically predicted short sleep (odds ratio = 1.87 and p = .02), and genetically predicted insomnia (odds ratio = 1.17 and p = .001) were causally associated with increased odds of coronary artery disease. Genetically predicted long sleep (odds ratio = 0.06 and p = .02) and genetically predicted longer sleep duration (odds ratio = 0.36 for per-hour increase in sleep duration and p = .0006) were causally associated with decreased odds of sudden cardiac arrest. CONCLUSIONS: The findings of this Mendelian randomization study indicate that insomnia and short sleep contribute to the development of coronary artery disease, whereas a longer sleep duration protects from sudden cardiac arrest, independent of the influence of obesity. The mechanisms underlying these associations warrant further investigation.

Differential relationships of NMDAR hypofunction and oxidative stress with cognitive decline.

NMDAR hypofunction and oxidative stress are implicated in the pathogenesis of Alzheimer's disease. D-amino acid oxidase (DAO) regulates NMDAR function. Glutathione, superoxide dismutase, and catalase are three first-line endogenous antioxidants. This study explored the associations of these potential biomarkers with mild cognitive impairment. Cognitive function and blood levels of DAO, glutathione, superoxide dismutase, and catalase were measured in 63 mild cognitive impairment patients and 24 healthy individuals every 6 months for 2 years. Among the patients, DAO and glutathione levels at baseline contributed to the cognitive decline 2 years later. Among the healthy individuals, only glutathione levels were associated with cognitive change. The four biomarkers differed in change directions (upward vs. downward) in the patients and in the healthy individuals. Among patients, glutathione levels were negatively correlated with superoxide dismutase and positively correlated with catalase, and DAO levels were negatively correlated with superoxide dismutase. To our knowledge, this is the first study to demonstrate the differential associations of NMDAR hypofunction and oxidative stress with cognitive change between the mild cognitive impairment patients and healthy people. Glutathione may be regarded as an aging marker for both mild cognitive impairment and normal aging; and DAO, a biomarker exclusively for mild cognitive impairment.

Associations between antenatal education program and mental health outcomes in Taiwan: A population-based cohort study.

Universal antenatal education has been offered to expectant mothers in Taiwan since 2014. Depression screening is included in the offered education sessions. This study aimed to examine the association of antennal education and depression screening with mental health outcomes, including perinatal depression diagnosis and psychiatrist visits. Data was obtained from the antenatal education records and Taiwan's National Health Insurance claims database. A total of 789,763 eligible pregnant women were included in the current study. The psychiatric-related outcomes were measured between antenatal education and the six-month after delivery. It was found that the antenatal education was widely used in Taiwan, and the attendance rate has increased to 82.6% since its launch. The attenders were more likely to be from disadvantaged backgrounds, and 5.3% of them were screened positive for depressive symptoms. They were also more likely to visit a psychiatrist but less likely to be diagnosed with depression than the non-attenders. Factors including young age, high healthcare utilization, and comorbid psychiatric disorder history were consistently associated with depression symptoms, perinatal depression diagnoses and psychiatrist visits. Further research is needed to understand the reasons for the nonattendance at antenatal education programmes and the barriers to utilizing mental health services.

Extremely Low Dose of Erythropoiesis-Stimulating Agent May Be Associated with Increased Mortality in Hemodialysis Patients.

INTRODUCTION: Although high-dose erythropoiesis-stimulating agent (ESA) has been shown to increase mortality risk and adverse cardiovascular events in hemodialysis patients, the safety of extremely low-dose ESA is unclear. METHODS: We retrospectively analyzed the association between ESA dose and mortality in the monthly dosing range of 0-43,000 U of equivalent epoetin alfa in 304 Taiwan hemodialysis patients by using Cox proportional hazard model and cubic spline model. RESULTS: Compared with mean monthly ESA dose of 15,000-25,000 U (mean ± standard deviation 20,609 ± 2,662 U), monthly ESA dose of less than 15,000 U (mean ± standard deviation 7,413 ± 4,510 U) is associated with increased mortality. Monthly ESA dose of 25,001-43,000 U (mean ± standard deviation 31,160 ± 4,304 U) is not associated with higher mortality risk than monthly ESA dose of 15,000-25,000 U. The results were consistent in Cox proportional hazard models and cubic spline models. Subgroup analyses showed no significant heterogeneities among prespecified subgroups. CONCLUSIONS: Extremely low dose of ESA in hemodialysis patients may be associated with increased mortality risk. Future studies are warranted to prove this association.

Endogenous antioxidants predicted outcome and increased after treatment: A benzoate dose-finding, randomized, double-blind, placebo-controlled trial for Alzheimer's disease.

AIM: Previous pilot studies suggest that sodium benzoate may be a potential cognitive enhancer for patients with Alzheimer's disease (AD), schizophrenia, or late-life depression. Especially for AD treatment, a confirmatory trial with predictive biomarkers is urgently needed. This study aimed to confirm benzoate as a novel treatment for AD and to discover its optimal dose and biomarkers. METHODS: A 24-week, dose-finding, randomized, double-blind, placebo-controlled trial, with clinical measurements at weeks 0, 8, 16, and 24, was conducted in three major medical centers in Taiwan. Among 154 patients screened for AD, 149 were eligible and randomized to one of the four treatments: (i) benzoate 500 group (fixed 500 mg/day); (ii) benzoate 750 (500 mg/day for the first 4 weeks, 750 mg/day from the 5th week); (iii) benzoate 1000 (500 mg/day for the first 4 weeks, 1000 mg/day from the 5th week); and (iv) placebo. The primary outcome measure was AD assessment scale-cognitive subscale (ADAS-cog). RESULTS: The benzoate 1000 group performed best in improving ADAS-cog (P = 0.026 at week 24), with female advantage. Higher plasma catalase at baseline predicted better outcome. Benzoate receivers tended to have higher catalase and glutathione than placebo recipients after treatment. The four intervention groups showed similar safety profiles. CONCLUSIONS: By enhancing two vital endogenous antioxidants, catalase and glutathione, sodium benzoate therapy improved cognition of patients with AD, with higher baseline catalase predicting better response. Supporting the oxidative stress theory, the results show promise for benzoate as a novel treatment for AD.

Associations of polygenic risks, depression, and obesity-related traits in Taiwan Biobank.

BACKGROUND: The comorbidity of obesity and major depressive disorder (MDD) may be attributable to a bidirectional relationship and shared genetic influence. We aimed to examine the polygenic associations between obesity and MDD and to characterize their corresponding impacts on the obesity mechanism. METHODS: Genome-wide genotyping was available in 106,604 unrelated individuals from Taiwan Biobank. Polygenic risk score (PRS) for body mass index (BMI) and MDD was derived to evaluate their effects on obesity-related traits. Stratified analyses were performed for the modified effect of depression on the polygenic associations. RESULTS: The MDD PRS was positively associated with waistline (beta in per SD increase in PRS = 0.12), hipline (beta = 0.08), waist-hip ratio (WHR) (beta = 0.05), body fat rate (beta = 0.08), BMI (beta = 0.05), overweight (OR = 1.02 for BMI ≥ 25), and obesity (OR = 1.05 for BMI ≥ 30). For the synergism between depression and BMI PRS, the presence of active depression symptoms defined by the PHQ-4 (p for interaction < 0.05 for waistline, WHR, and BMI) was more salient than lifetime MDD. LIMITATIONS: Limitations include recall bias for MDD due to a retrospective self-reporting questionnaire, a low response rate of the PHQ-4 for evaluating active psychological symptoms, and limited generalizability to non-Taiwanese ancestries. CONCLUSIONS: The shared genetic etiology of obesity and depression was demonstrated. The amplified effect of BMI polygenic effect on obesity for individuals with active depressive symptoms was also characterized. The study may be helpful for designing public health interventions to reduce the disease burden caused by obesity and depression.

Evaluation of the causal relationship between smoking and schizophrenia in East Asia.

Cigarette smoking has been suggested to be associated with the risk of schizophrenia in observational studies. A significant causal effect of smoking on schizophrenia has been reported in European populations using the Mendelian randomization approach; however, no evidence of causality was found in participants from East Asia. Using Taiwan Biobank (TWBB), we conducted genome-wide association studies (GWAS) to identify susceptibility loci for smoking behaviors, including smoking initiation (N = 79,989) and the onset age (N = 15,582). We then meta-analyzed GWAS from TWBB and Biobank Japan (BBJ) with the total sample size of 245,425 for smoking initiation and 46,000 for onset age of smoking. The GWAS for schizophrenia was taken from the East Asia Psychiatric Genomics Consortium, which included 22,778 cases and 35,362 controls. We performed a two-sample Mendelian randomization to estimate the causality of smoking behaviors on schizophrenia in East Asia. In TWBB, we identified one locus that met genome-wide significance for onset age. In a meta-analysis of TWBB and BBJ, we identified two loci for smoking initiation. In Mendelian randomization, genetically predicted smoking initiation (odds ratio (OR) = 4.00, 95% confidence interval (CI) = 0.89-18.01, P = 0.071) and onset age (OR for a per-year increase = 0.96, 95% CI = 0.91-1.01, P = 0.098) were not significantly associated with schizophrenia; the direction of effect was consistent with European Ancestry samples, which had higher statistical power. These findings provide tentative evidence consistent with a causal role of smoking on the development of schizophrenia in East Asian populations.

Paternal age and 13 psychiatric disorders in the offspring: a population-based cohort study of 7 million children in Taiwan.

Although paternal age has been linked to certain psychiatric disorders, the nature of any causal relationship remains elusive. Here, we aimed to comprehensively assess the magnitude of a wide range of offspring's psychiatric risk conferred by paternal age, leveraging a pedigree inferred from covered-insurance relationship (accuracy >98%) in Taiwan's single-payer compulsory insurance program. We also examined whether there is an independent role of paternal age and explored the potential effect of parental age difference. A total cohort of 7,264,788 individuals born between 1980 and 2018 were included; 5,572,232 with sibling(s) were selected for sibling-comparison analyses and 1,368,942 and 1,044,420 children with information of paternal-grandparents and maternal-grandparents, respectively, were selected for multi-generation analyses. Using inpatient/outpatient claims data (1997-2018), we identified schizophrenia, autism, bipolar disorder (BPD), attention deficit-hyperactivity disorder (ADHD), major depressive disorder (MDD), eating disorder (ED), substance use disorder (SUD), mental retardation (MR), tic disorder, obsessive-compulsive disorder (OCD), anxiety, and somatoform disorder. We identified suicides using death certificates. Logistic regression analysis was used to estimate the paternal/maternal/grand-paternal age association with psychiatric risk in the offspring. The total cohort and sibling-comparison cohort resulted in similar estimates. Paternal age had a U-shaped relationship with offspring's MDD, ED, SUD, and anxiety. A very young maternal age (<20 years) was associated with markedly higher risk in offspring's SUD, MR, and suicide. Older paternal age (>25 years) was linearly associated with offspring's schizophrenia, autism, BPD, ADHD, MDD, ED, SUD, MR, OCD, anxiety, and suicide. Older grand-paternal age was linearly associated with offspring's schizophrenia, autism, ADHD, and MR. Dissimilar parental age was positively associated with offspring's ADHD, MDD, SUD, MR, anxiety, and suicide, and negatively associated with offspring's OCD. This comprehensive assessment provides solid evidence for the independent role of paternal age in psychiatric risk in the offspring and clarifies the significance of both early parenthood and delayed paternity.

Causality of abdominal obesity on cognition: a trans-ethnic Mendelian randomization study.

BACKGROUND: Obesity has been associated with cognition in observational studies; however, whether its effect is confounding or a reverse causality remains inconclusive. This study aimed to investigate the causal relationships of overall obesity, measured by body mass index (BMI), and abdominal adiposity, measured by waist-hip ratio adjusted for BMI (WHRadjBMI), and cognition across European and Asian populations using Mendelian randomization (MR) analysis. METHODS: We used publicly available genome-wide association study (GWAS) summary data of European ancestry, including BMI (n = 322,154) and WHRadjBMI (n = 210,088) from the GIANT consortium, and cognition performance (n = 257,828) from the UK Biobank and COGENT consortium. Data for individuals of Asian ancestry were retrieved from Taiwan Biobank to perform GWAS for BMI (n = 65,689), WHRadjBMI (n = 65,683), and Mini-Mental State Examination (MMSE, n = 21,273). MR analysis was carried out using the inverse-variance weighted method for the main results. Further, we examined the overall pleiotropy by MR-Egger intercept, and detected and adjusted for possible outliers using MR PRESSO. RESULTS: No causal effect of BMI on cognition performance (beta [95% CI] = 0.00 [-0.07, 0.07], p value = 0.91) was found for Europeans; however, a 1-SD increase in WHRadjBMI was associated with a 0.07 standardized score decrease in cognition performance (beta [95% CI] = -0.07 [-0.12, -0.02], p value = 0.006). Further, no causal effect of BMI on MMSE (beta [95% CI] = 0.01 [-0.08, 0.10], p = 0.91) was found for Asians; however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized score decrease in MMSE (beta [95% CI] = -0.17 [-0.30, -0.03], p = 0.02). In both populations, overall pleiotropy was not detected, and outliers did not affect the robustness of the main findings. CONCLUSIONS: This trans-ethnic MR study reveals that abdominal adiposity, as measured by WHR adjusted for BMI, impairs cognition, whereas weak evidence suggests that BMI impairs cognition.

Familial aggregation and shared genetic loading for major psychiatric disorders and type 2 diabetes.

AIMS/HYPOTHESIS: Psychiatric disorders, such as schizophrenia (SCZ), major depressive disorder (MDD) and bipolar disorder (BPD), are highly comorbid with type 2 diabetes. However, the mechanisms underlying such comorbidity are understudied. This study explored the familial aggregation of common psychiatric disorders and type 2 diabetes by testing family history association, and investigated the shared genetic loading between them by testing the polygenic risk score (PRS) association. METHODS: A total of 105,184 participants were recruited from the Taiwan Biobank, and genome-wide genotyping data were available for 95,238 participants. The Psychiatric Genomics Consortium-derived PRS for SCZ, MDD and BPD was calculated. Logistic regression was used to estimate the OR with CIs between a family history of SCZ/MDD/BPD and a family history of type 2 diabetes, and between the PRS and the risk of type 2 diabetes. RESULTS: A family history of type 2 diabetes was associated with a family history of SCZ (OR 1.23, 95% CI 1.08, 1.40), MDD (OR 1.19, 95% CI 1.13, 1.26) and BPD (OR 1.26, 95% CI 1.15, 1.39). Compared with paternal type 2 diabetes, maternal type 2 diabetes was associated with a higher risk of a family history of SCZ. SCZ PRS was negatively associated with type 2 diabetes in women (OR 0.92, 95% CI 0.88, 0.97), but not in men; the effect of SCZ PRS reduced after adjusting for BMI. MDD PRS was positively associated with type 2 diabetes (OR 1.04, 95% CI 1.00, 1.07); the effect of MDD PRS reduced after adjusting for BMI or smoking. BPD PRS was not associated with type 2 diabetes. CONCLUSIONS/INTERPRETATION: The comorbidity of type 2 diabetes with psychiatric disorders may be explained by shared familial factors. The shared polygenic loading between MDD and type 2 diabetes implies not only pleiotropy but also a shared genetic aetiology for the mechanism behind the comorbidity. The negative correlation between polygenic loading for SCZ and type 2 diabetes implies the role of environmental factors.