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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.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.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 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.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.

Background Whether paternal age effect on schizophrenia is a causation or just an association due to confounding by selection into late parenthood is still debated. We investigated the association between paternal age and early onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia as empirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium. Methods Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research in Taiwan project, 1649 had parents’ genotyping data. The relationships of paternal schizophrenia PRS to paternal age at first birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model of patients’ early onset of schizophrenia (≤18 years old) on paternal age was conducted. Results Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset of schizophrenia (odds ratio per 10-year increase in paternal age = 1.28, p = .007) after adjusting for maternal age, sex, and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, a U-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting for both paternal and maternal schizophrenia PRS, the association of paternal age with patients’ early onset of schizophrenia remained (odds ratio = 1.29, p = .04). Conclusions The association between paternal age and early onset of schizophrenia was not confounded by parental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Our findings support an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring.

Prenatal perfluoroalkyl substance (PFAS) exposure has been linked to adverse birth outcomes, but the underlying mechanism has yet to be elucidated. DNA methylation changes in mesoderm-specific transcript (MEST) imprinted gene may be a mechanism of the prenatal exposure effects of PFASs on fetal growth. The aim was to investigate the prenatal PFASs exposure effects on DNA methylation changes in MEST imprinted gene involved in fetal growth. Among 486 mother-infant pairs from the Taiwan Birth Panel Study, PFASs and DNA methylation levels at 5 CpG sites of MEST promoter region were measured in cord blood. Univariable and multivariable linear regressions were performed to estimate the associations between prenatal PFAS exposure, MEST DNA methylation levels, and child birth outcomes. Mediation analysis was performed to examine the potential pathway of MEST methylation between PFASs and birth outcomes. We found that higher prenatal perfluorooctyl sulfonate (PFOS) exposure was significantly associated with lower methylation levels at 5 CpG sites of MEST promoter region (an adjusted β range: -1.56, -2.22). Significant negative associations were also found between MEST methylation levels and child birth weight. Furthermore, the associations between PFOS and perfluorooctanoic acid (PFOA) exposure and MEST methylation levels were more profound in girls than in boys. The mediated effect of average MEST methylation level between PFOS exposure and birth weight was 18.3 (95% CI = 2.1, 40.2; p = 0.014). The direct effect of PFOS exposure to birth weight independent to average MEST methylation level was -93.2 (95% CI = -170.5, -17.8; p = 0.018). In conclusion, our results suggest that prenatal PFAS exposure, especially PFOS, is associated with lower methylation levels at MEST promoter region, which not only leverages the role of imprinted gene in ensuring the integrity of fetal growth but also provides a potential mechanism for evaluating the prenatal exposure effect.

In utero perfluoroalkyl substances (PFASs) exposures have been linked to adverse birth outcomes, but the underlying mechanism remains elusive. Epigenetic regulations such as changes in DNA methylation profiles in mesoderm-specific transcript (MEST) imprinted gene may provide a potential mechanism of the prenatal exposure effects of PFASs on fetal growth. The aim of the study was to investigate the prenatal exposure effects of PFASs to DNA methylation changes at MEST imprinted gene involved in fetal growth. A total of four hundred and eighty-six mother-infant pairs were included in the analyses from Taiwan Birth Panel Study (TBPS), collecting from 2004 to 2005 in four hospitals in Taipei city and New Taipei City. PFASs were measured by UPLC-MS/MS in cord blood. DNA methylation levels of MEST gene were measured from cord blood. Univariable and multivariable linear regressions were performed to estimate the associations between prenatal PFASs exposures, MEST DNA methylation levels, and the child birth outcomes. Mediation analysis was performed to examine the potential pathway of MEST methylation in the relationship between PFASs and birth outcomes. We found that higher prenatal exposures to perfluorooctyl sulfonate (PFOS) was significantly associated with lower methylation levels at 5 CpG sites of MEST promoter region, after considering potential confounding factors. Significant negative associations were also found between MEST methylation levels and child birth weight. Gender difference was observed in the association between PFASs exposure and MEST methylation level. Prenatal PFOS exposure effect on birth weight might be mediated by MEST methylation. In conclusion, our results suggest that prenatal PFASs exposures, especially PFOS, are associated with lower methylation levels at MEST promoter region, which not only leverage the role of imprinted gene for ensuring the integrity of fetal growth but also provide a potential mechanism for evaluating the prenatal exposure effect. Funding Information: This work was supported by the National Taiwan University Higher Education Sprout Project (NTU-110L8810) within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) and the Ministry of Science and Technology (MOST 103-2633-B-002-013-, MOST 104-2633-B-002-007-) in Taiwan. Declaration of Interests: The authors declare they have no actual or potential competing financial interests. Ethics Approval Statement: Ethical approval of the study was obtained from the Independent Ethics Committee of National Taiwan University Hospital. Informed consent from the pregnant women was obtained before giving birth.

Hepatocellular carcinogenesis of hepatitis B virus (HBV) infection may arise from integration of viral DNA into the host genome. We aimed to gauge the effect of viral inhibition on transcriptionally active HBV-host integration events and explore the correlation of viral integrations with host gene dysregulation.We leveraged data and biospecimens from an interventional trial, in which patients with HBV viremia above 2000 IU/mL and minimally raised serum liver enzyme were randomized to receive tenofovir disoproxil fumarate (TDF) or placebo for 3 years. Total RNA-sequencing was performed on paired liver biopsies taken before and after the 3-year intervention in 119 patients. Virus-host chimeric reads were captured to quantify the number of distinct viral integrations. Dysregulation of a host gene disrupted by viral integration was defined by aberrant expression2 standard deviations away from samples without viral integration.The TDF (n = 64) and placebo groups (n = 55) were comparable at baseline. Expressed viral integrations were detected in all pre- and posttreatment samples. The number of distinct viral integrations significantly correlated with circulatory biomarkers indicative of viral activities including HBV DNA, RNA, and viral antigens (P.0003 for all correlations). Moreover, TDF vs placebo achieved a significantly greater reduction in distinct viral integrations, with 3.28-fold and 1.81-fold decreases in the expressed integrations per million reads, respectively (analysis of covariance, P = .037). Besides, viral integrations significantly correlated with host gene dysregulation.Inhibition of viral replication reduces the number of transcriptionally active distinct HBV-host DNA integrations in patients with substantial viremia. Given the mutagenic potentials of viral integrations, such treatment effects should be considered in patient management.

s Objective To explore the causal effect of time-varying z-BMI growth on early menarche using Mendelian randomisation (MR); to identify critical adiposity predictors of early menarche; to compare the effects of birthweight and time-varying z-BMI growth as mediators of the path from genes to early menarche using mediation analysis. Methods We used data from the Taiwan Children Health Study with 21 obesity-related single-nucleotide polymorphisms (SNPs) to yield genetic (instrumental variable)IVs for adiposity. Children with available data on genotyping, birthweight, adiposity, and menarcheal age were included. Results In MR analyses, results based on the time-varying z-BMI growth show more statistical power and capture more information of adiposity growth (p = 0.01) than those based on single point z-BMI (p = 0.02). Among adiposity measures, critical predictors of early menarche are fat free mass (RR = 1.33, 95% CI 1.07–1.65) and waist/height ratio (RR = 1.27, 95% CI 1.03–1.56). Other potential predictors of early menarche are sum of skinfold (RR = 1.24, 95% CI 1.03–1.48) and total body fat (RR = 1.20, 95% CI 1.05–1.38). In both one-mediation and multi-mediation analyses, time-varying z-BMI growth in the prepubertal years plays a crucial mediator in the pathway from the genes to early menarche. Conclusions This study discovered that greater prepubertal adiposity growth is a crucial mediator in the path from genes to early menarche. For girls with genes positively associated with obesity; and/or of lower birthweight, a strategy to prevent childhood adiposity should be implemented in order to avoid early menarche development.

The heart actively remodels architecture in response to various physiological and pathological conditions. Gross structural change of the heart chambers is directly reflected at the cellular level by altering the morphological characteristics of individual cardiomyocytes. However, an understanding of the relationship between cardiomyocyte shape and the contractile function remains unclear. By using in vitro assays to analyze systolic stress of cardiomyocytes with controlled shape, we demonstrated that the characteristic morphological features of cardiomyocytes observed in a variety of pathophysiological conditions are correlated with mechanical performance. We found that cardiomyocyte contractility is optimized at the cell length/width ratio observed in normal hearts, and decreases in cardiomyocytes with morphological characteristics resembling those isolated from failing hearts. Quantitative analysis of sarcomeric architecture revealed that the change of contractility may arise from alteration of myofibrillar structure. Measurements of intracellular calcium in myocytes revealed unique characteristics of calcium metabolism as a function of myocyte shape. Our data suggest that cell shape is critical in determining contractile performance of single cardiomyocytes by regulating the intracellular structure and calcium handling ability.