Jing Yang's research while affiliated with Zhengzhou University and other places

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.

Evidence linking sleep timing and night sleep duration to dyslipidemia was limited and inconclusive, especially among low- and middle-income adults. The aims were to evaluate the associations between sleep timing, night sleep duration and dyslipidemia in a rural population. Based on the Henan Rural Cohort Study, a total of 37 164 participants were included. The Pittsburgh Sleep Quality Index was used to collect sleep information. Logistic regression and restrictive cubic splines were conducted to explore the associations. Of the 37 164 enrolled participants, 13881 suffered from dyslipidemia. Compared to the reference groups, people who went to sleep after 23:00 or woke up after 7:30 had higher prevalence of dyslipidemia, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs)were 1.30 (1.20-1.41) and 1.34 (1.19-1.50). The adjusted OR (95%CI) of participants in the Late-sleep/Late-rise category compared to the Early-sleep/Early-rise category was 1.55 (1.08-1.23). Compared to the reference (7~≤8 h), the adjusted OR (95%CI) was 1.11 (1.03-1.20) for longer (>9 h) night sleep duration. Moreover, the combined effects of sleep duration (>9 h) with sleep time (22:00~) (OR = 1.46, 95%CI: 1.16-1.84), sleep duration (>9 h) with wake-up time (≥7:30) (OR = 1.28, 95%CI: 1.08-1.51), and sleep duration (>9 h) with the Late-sleep/Late-rise category (OR = 1.41, 95%CI: 1.14-1.75) increased the prevalence of dyslipidemia. Accordingly, our results indicate that delayed sleep timing and longer night sleep duration had independent and joint effects on higher risks of dyslipidemia in rural population.

Introduction To evaluate the effect of age at menarche on metabolic syndrome (Mets) and its components and explore the impact of menopause status on the association between age at menarche and Mets in rural Chinese women. Methods This cross-sectional study enrolled 23382 women from the Henan Rural Cohort study. The relationship between age at menarche and Mets was assessed using logistic regression and restricted cubic spline. Interaction plots were used to describe interactive effects of age at menarche and menopause status on Mets. Results Age at menarche was inversely associated with the risk of Mets with the adjusted OR of 1.16, 0.98, 1.00, 0.82, and 0.77, respectively, for those with age at menarche≤13, 14, 15–16 (reference), 17, and≥18 years. Each year of delay in menarche age correlated with a 6.2% (P<0.001) lower risk of Mets. Among the components of Mets, an inverse association was observed between age at menarche and central obesity (OR (95% CI): 0.92 (0.90, 0.94)), abnormal FPG (OR (95% CI): 0.96 (0.94, 0.97)), abnormal BP (OR (95% CI): 0.967 (0.95, 0.98)), abnormal TG (OR (95% CI): 0.96 (0.94, 0.97)), and abnormal HDL-C (OR (95% CI): 0.96 (0.95, 0.98)). Significant interactions were discovered between age at menarche, menopause status, and the risk of Mets, central obesity, abnormal FPG, abnormal BP, and abnormal TG (all P interaction<0.001). The adverse effect of menopausal status on Mets, central obesity, abnormal FPG, abnormal BP, and abnormal TG decreased with delayed age at menarche. Conclusions Later menarche was associated with a lower risk of Mets. More importantly, the deleterious effect of menopause status on Mets decreased with the increase in age at menarche.

Amyloid-β (Aβ) plays an important role in the neuropathology of Alzheimer’s disease (AD), but some factors promoting Aβ generation and Aβ oligomers (Aβos) neurotoxicity remain unclear. We here found that the levels of ArhGAP11A, a Ras homology GTPase activating protein, significantly increased in AD patients and APP/PS1 mice. Reducing ArhGAP11A level in neurons not only inhibited Aβ generation by decreasing the expression of APP, PS1 and BACE1 through RhoA/ROCK/Erk signaling pathway, but also reduced Aβos neurotoxicity by decreasing the expressions of apoptosis-related p53 target genes. In APP/PS1 mice, specific reduction of ArhGAP11A level in neurons significantly reduced Aβ production and plaque deposition, and ameliorated neuronal damage, neuroinflammation and cognitive deficits. Moreover, Aβos enhanced ArhGAP11A expression in neurons by activating E2F1, which thus forms a deleterious cycle . Our results demonstrate that ArhGAP11A may be involved in AD pathogenesis, and decreasing ArhGAP11A expression should be a promising therapeutic strategy for AD treatment.

Introduction The purpose of this study was to investigate the relationship between first pregnancy age and hypertension later in the life of women from Chinese rural areas. Methods In total, 13,493 women were enrolled in the Henan Rural Cohort study. Logistic regression and linear regression were used to evaluate the association between first pregnancy age and hypertension and blood pressure indicators [including systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP)]. The restricted cubic spline was used to examine the dose–response relationship between the first pregnancy age and hypertension or blood pressure indicators. Results After adjusting for potential confounders, each 1-year increase in first pregnancy age was associated with a 0.221 mmHg increase in SBP values, a 0.153 mmHg increase in DBP values, and a 0.176 mmHg decrease in MAP values (all P < 0.05). The β of SBP, DBP, and MAP showed a trend of first increasing and then decreasing with increasing first pregnancy age and there was no statistical significance after first pregnancy age beyond 33 years on SBP, DBP, and MAP, respectively. A 1-year increment in first pregnancy age was associated with a 2.9% [OR (95% CI): 1.029 (1.010, 1.048)] higher odds of prevalent hypertension. The odds of hypertension increased sharply and then eventually leveled off with an increment of first pregnancy age after adjusting for potential confounders. Conclusion First pregnancy age might increase the risk of hypertension later in life and might be an independent risk factor for hypertension in women.

Background Evidence has suggested the linkage between sleep habits and several metabolic diseases, but the association of sleep factors with bone health remains unclear, especially in regions with low economic levels. Thus, this study aimed to investigate the relationship of nocturnal sleep duration and sleep midpoint with the osteoporosis risk in a rural population. Method Eligible subjects were derived from the Henan Rural Cohort Study. The Pittsburgh Sleep Quality Index was applied to collect sleep information including sleep initiating time and wake-up time. The bone mineral density of the calcaneus was measured by the ultrasonic bone density apparatus. Multivariable logistic regression models and restricted cubic splines were utilized to evaluate the odds ratio (OR) and 95% confidence intervals (95% CI). Results For 8033 participants, 1636 subjects suffered from osteoporosis. Compared with the reference group (7 ~ h group), the ORs and 95% CI of osteoporosis associated with duration of nocturnal sleep were 1.32 (1.10, 1.56), 1.59 (1.25, 2.01), and 1.82 (1.25, 2.65) in the 8 ~ h, 9 ~ h, and ≥ 10 h group, respectively. Additionally, the adjusted ORs and 95% CI were 1.20 (1.01, 1.44) in the early sleep midpoint group and 1.09 (0.92, 1.29) in the intermediate sleep midpoint, compared with the late. Furthermore, there was a joint effect of long duration of nocturnal sleep and the early sleep midpoint on osteoporosis. Conclusion Long duration of nocturnal sleep and early sleep midpoint were independently and jointly associated with higher risk of osteoporosis in rural areas. Trial registration The Henan Rural Cohort Study has been registered at Chinese Clinical Trial Register (Registration number: ChiCTR-OOC-15006699). Date of registration: 06 July 2015. http://www.chictr.org.cn/showproj.aspx?proj=11375

GGC repeat expansion in the 5′ untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific iPSC-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response, and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis, and induce ribosomal RNA (rRNA) sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

Background The purpose of this study was to investigate the relationship of duration of reproductive period with metabolic syndrome (MetS) and its components in rural population. Methods In all, 14596 menopausal women were enrolled from the Henan Rural Cohort study. Logistic regression and linear regression were used to evaluate the association between duration of reproductive period and MetS and its components (including central obesity, abnormal fasting plasma glucose (FPG), abnormal blood pressure (BP), abnormal triglycerides (TG) and abnormal high-density lipoprotein cholesterol (HDL-C). In addition, the mediation and interaction effects were performed by mediation analyses and generalized linear model. Results Each year of increase reproductive period correlated with an increased risk of MetS (OR = 1.031; 95% CI = 1.023–1.039; P < 0.05). This association changed slightly after adjusting for body mass index (BMI) and remained statistically significant (OR (95% CI): 1.012(1.003, 1.021)). A positive association between duration of reproductive period and central obesity, abnormal FPG, abnormal BP, abnormal TG, and abnormal HDL-C were revealed (all P < 0.05). The relationship with abnormal FPG (OR (95% CI): 1.009(1.000, 1.017)) and abnormal TG (OR (95% CI): 1.013(1.005, 1.021)) were attenuated after adjusting for BMI and remained statistically significant except for central obesity, abnormal BP and abnormal HDL-C. In addition, BMI mediated the relationship between duration of reproductive period and MetS and its components. The significant interaction of high fat diet was found in association between duration of reproductive period and MetS (P interaction = 0.011). Conclusions The longer duration of reproductive period might raise a woman's risk of MetS and its components. More importantly, the association was largely mediated by BMI. There is an interaction effect between duration of reproductive period and high fat diet on the risk of MetS.