Genomic analyses of 10,376 individuals in the Westlake BioBank for Chinese (WBBC) pilot project.

We initiate the Westlake BioBank for Chinese (WBBC) pilot project with 4,535 whole-genome sequencing (WGS) individuals and 5,841 high-density genotyping individuals, and identify 81.5 million SNPs and INDELs, of which 38.5% are absent in dbSNP Build 151. We provide a population-specific reference panel and an online imputation server ( https://wbbc.westlake.edu.cn/ ) which could yield substantial improvement of imputation performance in Chinese population, especially for low-frequency and rare variants. By analyzing the singleton density of the WGS data, we find selection signatures in SNX29, DNAH1 and WDR1 genes, and the derived alleles of the alcohol metabolism genes (ADH1A and ADH1B) emerge around 7,000 years ago and tend to be more common from 4,000 years ago in East Asia. Genetic evidence supports the corresponding geographical boundaries of the Qinling-Huaihe Line and Nanling Mountains, which separate the Han Chinese into subgroups, and we reveal that North Han was more homogeneous than South Han.

Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density.

Bone mineral density (BMD) is a highly heritable complex trait and is a key indicator for diagnosis and treatment for osteoporosis. In the last decade, numerous susceptibility loci for BMD and fracture have been identified by genome-wide association studies (GWAS); however, fine mapping of these loci is challengeable. Here, we proposed a new long-range fine-mapping approach that combined superenhancers (SEs) and microRNAs (miRNAs) data, which were two important factors in control of cell identity and specific differentiation, with the GWAS summary datasets in cell-type-restricted way. Genome-wide SE-based analysis found that the BMD-related variants were significantly enriched in the osteoblast SE regions, indicative of potential long-range effects of such SNPs. With the SNP-mapped SEs (mSEs), 13 accessible long-range mSE-interacted miRNAs (mSE-miRNAs) were identified by integrating osteoblast Hi-C and ATAC-seq data, including three known bone-related miRNAs (miR-132-3p, miR-212-3p and miR-125b-5p). The putative targets of the two newly identified mSE-miRNAs (miR-548aj-3p and miR-190a-3p) were found largely enriched in osteogenic-related pathway and processes, suggesting that these mSE-miRNAs could be functional in the regulation of osteoblast differentiation. Furthermore, we identified 54 genes with the long-range 'mSE-miRNA' approach, and 24 of them were previously reported to be related to skeletal development. Besides, enrichment analysis found that these genes were specifically enriched in the post-transcriptional regulation and bone formation processes. This study provided a new insight into the approach of fine-mapping of GWAS loci. A tool was provided for the genome-wide SE-based analysis and the detection of long-range osteoblast-restricted mSE-miRNAs (https://github.com/Zheng-Lab-Westlake/Osteo-Fine-Mapp-SNP2SE2miRNA).

Cohort profile: the Westlake BioBank for Chinese (WBBC) pilot project.

PURPOSE: The Westlake BioBank for Chinese (WBBC) pilot cohort is a population-based prospective study with its major purpose to better understand the effect of genetic and environmental factors on growth and development from adolescents to adults. PARTICIPANTS: A total of 14 726 participants (4751 males and 9975 females) aged 14-25 years were recruited and the baseline survey was carried out from 2017 to 2019. The pilot cohort contains rich range of information regarding of demographics and anthropometric measurements, lifestyle and sleep patterns, clinical and health outcomes. Visit the WBBC website for more information (https://wbbc.westlake.edu.cn/index.html). FINDINGS TO DATE: The mean age of the study samples were 18.6 years for males and 18.5 years for females, respectively. The mean height and weight were 172.9 cm and 65.81 kg for males, and 160.1 cm and 52.85 kg for females. Results indicated that the prevalence of underweight in female was much higher than male, but the prevalence of overweight and obesity in female was lower than male. The mean serum 25(OH)D level in the 14 726 young participants was 22.4±5.3 ng/mL, and male had a higher level of serum 25(OH)D than female, overall, 33.5% of the participants had vitamin D deficiency and even more participants suffered from vitamin D insufficiency (58.2%). The proportion of deficiency in females was much higher than that in males (41.8 vs 16.4%). The issue of underweight and vitamin D deficiency in young people should be paid attention, especially in females. These results reflected the fact that thinness and paler skin are preferred in modern aesthetics of Chinese culture. FUTURE PLANS: WBBC pilot is designed as a prospective cohort study and provides a unique and rich data set analysing health trajectories from adolescents to young adults. WBBC will continue to collect samples with old age.

Systemic evaluation of the relationship between psoriasis, psoriatic arthritis and osteoporosis: observational and Mendelian randomisation study.

OBJECTIVES AND METHODS: With 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them. RESULTS: Lower eBMD were observed in patients with PsA than in controls in both model0 (ß-coefficient=-0.014, p=0.0006) and model1 (ß-coefficient=-0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (ß-coefficient=-0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (p<2E-16). Patients with psoriasis without arthritis showed no difference of eBMD compared with controls. Similarly, the significance of higher risk of osteopenia in patients with PsA (OR=1.27, p=0.002 in model0) could be eliminated by conditioning on medication treatment (p=0.244 in model2). Psoriasis without arthritis was not related to osteopenia and osteoporosis. The weighted Genetic Risk Score analysis found that genetically determined psoriasis/PsA were not associated with eBMD (p=0.24 and p=0.88). Finally, MR analysis showed that psoriasis/PsA had no causal effect on eBMD, osteoporosis and fracture. CONCLUSIONS: The effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis.

Identification of PIEZO1 polymorphisms for human bone mineral density.

Bone mineral density (BMD) is a key indicator for diagnosis and treatment for osteoporosis; the reduction of BMD could increase the risk of osteoporotic fracture. It was very recently found that Piezo1 mediated mechanically evoked responses in bone and further participated in bone formation in mice. Here, we performed cross phenotype meta-analysis for human BMD at lumbar spine (LS), femoral neck (FN), distal radius/forearm (FA) and heel and screened out 14 top SNPs for PIEZO1, these SNPs were overlapped with putative enhancers, DNase-I hypersensitive sites and active promoter flanking regions. We found that the signal of the best SNP rs62048221 was mainly from heel ultrasound estimated BMD (-0.02 SD per T allele, P = 8.50E-09), where calcaneus supported most of the mechanical force of body when standing, walking and doing physical exercises. Each copy of the effect allele T of SNP rs62048221 was associated with a decrease of 0.0035 g/cm2 BMD (P = 4.6E-27, SE = 0.0003) in UK Biobank data within 477,760 samples. SNP rs62048221 was located at the enhancer region (HEDD enhancer ID 2331049) of gene PIEZO1, site-directed ChIP assays in human mesenchymal stem cells (hMSCs) showed significant enrichment of H3K4me1 and H3K27ac in this region, luciferase assays showed that rs62048221 could significantly affect the activity of the enhancer where it resides. Our results first suggested that SNP rs62048221 might mediate the PIEZO1 expression level via modulating the activity of cis-regulatory elements and then further affect the BMD.

Effect of CD14 polymorphisms on the risk of cardiovascular disease: evidence from a meta-analysis.

BACKGROUND: CD14 polymorphisms are associated with an increased risk of cardiovascular events. So far, many studies have been conducted, whereas the results were not always consistent. MATERIALS AND METHODS: Twenty-six articles involving thirty-seven datasets were recruited to evaluate the association between rs2569190 (9413 patients and 7337 controls), C-159T (4813 patients and 2852 controls) polymorphisms and cardiovascular diseases in a meta-analysis. The random or fixed effect models were used to evaluate the pooled odds ratios (ORs) and their corresponding 95% confidence intervals. RESULTS: The strongest association was observed between rs2569190 and CVD in overall population (T vs. C, OR = 1.169, 95% CI: 1.087-1.257, p = 2.44 × 10- 5). Analysis after stratification by ethnicity indicated that rs2569190 was related to CVD in East Asian population (T vs. C, OR = 1.370, 95% CI; 1.226-1.531, p = 2.86 × 10- 8) and a potential relationship in European (T vs. C, OR = 1.100, 95% CI: 1.019-1.189, p = 0.015). In the stratification of endpoints, the associations were found in CHD subgroup (T vs. C, OR = 1.357, 95% CI: 1.157-1.592, p = 2.47 × 10- 7) and in AMI subgroup (T vs. C, OR = 1.152, 95% CI: 1.036-1.281, p = 0.009). However, we did not find any association between C-159T polymorphism with cardiovascular disease under any model. CONCLUSIONS: The SNP rs2569190 significantly contribute to susceptibility and development of cardiovascular disease, particularly in the East Asian population and in the subtype CHD group, in addition, a potential association was observed in the AMI group, T allele acts as a risk factor for cardiovascular disease.

Genotype imputation and reference panel: a systematic evaluation on haplotype size and diversity.

Here, 622 imputations were conducted with 394 customized reference panels for Han Chinese and European populations. Besides validating the fact that imputation accuracy could always benefit from the increased panel size when the reference panel was population specific, the results brought two new thoughts. First, when the haplotype size of the reference panel was fixed, the imputation accuracy of common and low-frequency variants (Minor Allele Frequency (MAF) > 0.5%) decreased while the population diversity of the reference panel increased, but for rare variants (MAF < 0.5%), a small fraction of diversity in panel could improve imputation accuracy. Second, when the haplotype size of the reference panel was increased with extra population-diverse samples, the imputation accuracy of common variants (MAF > 5%) for the European population could always benefit from the expanding sample size. However, for the Han Chinese population, the accuracy of all imputed variants reached the highest when reference panel contained a fraction of an extra diverse sample (8-21%). In addition, we evaluated the imputation performances in the existing reference panels, such as the Haplotype Reference Consortium (HRC), 1000 Genomes Project Phase 3 and the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE). For the European population, the HRC panel showed the best performance in our analysis. For the Han Chinese population, we proposed an optimum imputation reference panel constituent ratio if researchers would like to customize their own sequenced reference panel, but a high-quality and large-scale Chinese reference panel was still needed. Our findings could be generalized to the other populations with conservative genome; a tool was provided to investigate other populations of interest (https://github.com/Abyss-bai/reference-panel-reconstruction).

Comprehensive assessment of the association between genes on JAK-STAT pathway (IFIH1, TYK2, IL-10) and systemic lupus erythematosus: a meta-analysis.

Previous studies have reported that genes relating to JAK-STAT pathway (IFIH1, TYK2 and IL-10) conferred the susceptibility to SLE. In this study, we performed a meta-analysis (including 43 studies) to evaluate the association between IFIH1 (9288 patients and 24,040 controls), TYK2 (4928 patients and 11,536 controls), IL-10 (3623 patients and 4907 controls) polymorphisms and systemic lupus erythematosus (SLE) in a comprehensive way. We found that IFIH1 rs1990760_T allele was associated with risk of SLE in overall population under three models (allelic: P = 2.56 × 10-11, OR 1.135, 95% CI 1.094-1.179, dominant: P = 1.8 × 10-8, OR 1.203, 95% CI 1.128-1.284, recessive: P = 2.6 × 10-7, OR 1.163, 95% CI 1.098-1.231). A strong association had been observed between TYK2 polymorphism rs2304256_C allele and SLE in Europeans (P = 5.82 × 10-5, OR 1.434, 95% CI 1.203-1.710). When coming to overall population, TYK2 rs2304256_C showed a significant association with SLE under recessive model (P = 8.05 × 10-3, OR 1.314, 95% CI 1.074-1.608). However, the other two SNPs (rs12720270, rs280519) of TYK2 were not significant. The results also indicated an association between IL-10 rs1800896_G allele and SLE in Asians under recessive model (P = 4.65 × 10-3, OR 2.623, 95% CI 1.346-5.115), while, IL-10 rs1800896_G had a trend of association with SLE in European population in dominant model (P = 1.21 × 10-2, OR 1.375, 95% CI 1.072-1.764). In addition, we found IL-10 rs1800896 GG homozygote might be associated with increased susceptibility to SLE (GG vs AA, P = 4.65 × 10-3, OR 1.539, 95% CI 1.142-2.072). We concluded that IFIH1 rs1990760_T and TYK2 rs2304256_C alleles were significantly associated with SLE, and IL-10 rs1800896 GG homozygote might have an enhancement effect on SLE risk.

[Spectral Characteristics of Chromophoric Dissolved Organic Matter (DOM) from a Typical Reservoir Lake from Inland of Three Gorges Reservoir Areas: In the View of Riparian Ecosystem Analysis].

For further understanding the geochemical characteristics of dissolved organic matter (DOM) in "reservoir-type" lake, in this study a typical "reservoir-type" lake, Changshou Lake located in inlands of Three Gorges Reservoir areas, was selected to investigate the composition, sources and spatial distributions of chromophoric DOM (CDOM) in this lake, through UV-Vis and three-dimensional fluorescence spectroscopy combined within analysis of riparian eco-system differences. The results showed that DOM concentrations including dissolved organic carbon (DOC) and CDOM abundance in different sampling sites varied spatially to a certain degree, in contrast to fluorescence component of DOM showing a constant level. In backwater zone (also called stagnant zone alternatively), due to accumulation of DOM and limited impact of terrestrial contribution, the endogenesis (autochthonous production) was the predominant geochemical process showing an obvious "authigenic-control" characteristic, and relatively lower aromaticity and molecular weight. In comparison, sampling sites surrounding artificial forests and tourism development, the highly humic (highly aromatic) substances resulted from terrestrial inputs were the main source, but discharge due to human activities was also responsible for highly protein-like component observed in DOM. Additionally, in the entry zones of lake from upstream river, DOM was affected by fruit plantations and residences, contribution from upstream river could also be neglected. From the other aspects, some significant correlations were also observed, which were independent of riparian eco-system differences, for example, the SUVA280 versus S(275-295) (negative), CDOM versus FDOM (positive), and CDOM and S(275-295) (negative), indicating the correlation was an intrinsic property of DOM that could not be affected by the surrounding environment. Meanwhile, the main chromophoric component of CDOM in Changshou Lake was high molecular weight (HMW) components within highly aromatic structures. At least, 51% of CDOM dynamic could be explained by changes of FDOM, especially in backwater zone the co-variance was more obvious. Furthermore, when the traditional fluorescence index (FI) could not comprehensively explain the differences of DOM sources due to very similar (statistically insignificant) values, integration of UV-Vis and fluorescence spectral characteristics and detailed discussion of riparian eco-system differences, might be an important way to help further resolution of DOM composition and sources in aquatic environments, such as lake, river and watershed.

[Absorption Spectral Characteristic Dynamics of Dissolved Organic Matter (DOM) from a Typical Reservoir Lake in Inland of Three Gorges Reservoir Areas: Implications for Hg Species in Waters].

Dissolved organic matter (DOM) is an important component in lake eco-systems. It plays a crucial role in the environmental fate of pollutants such as mercury(Hg), because of its specific characteristics and functional structures. In this study, a typical reservoir lake from inland of Three Gorges Reservoir areas, Changshou Lake was selected to track the changes of DOM geochemical properties for one year by using UV-Vis absorption spectroscopy technique. Meanwhile, based on observed Hg data in Changshou Lake, it further validated the key environmental implications of DOM for Hg distributions in lake. The results showed that as compared to January, other months including April, June and September had significantly higher CDOM, but also higher DOC with a slightly decreasing significance. Dynamics of chromphoric component is an important reason to explain the seasonal changes of DOM concentration in Changshou Lake. Chromphores of DOM were mainly derived from high molecular weight (MW) materials with high aromaticity. Also, three wavelengths fitting model of CDOM could be used for inversion of DOC concentration in annual monitoring. Meanwhile, seasonal differences of SUVA254 and S275-295 were significant. Lowest aromaticity and MW size were observed in January following an obvious increase from April. In contrast to other types of lakes, DOM aromaticity and MW size in Changshou Lake were lower than forest lakes, but higher than plateau lakes. Eco-system and land use types surrounding lakes could have a heavily impact on the heterogeneous properties of DOM. Importantly, no clear differences between concentrations of Hg species and SUVA254 and DOC respectively were observed, however chromphoric component and MW size controlled the dissolved Hg and reactive Hg in lake. Additionally, enrichment and migration of organic matter resulted from primary productivity in lake may be a substantial reason to explain the methylmercury changes.

[Spatial Distribution Characteristics of Different Species Mercury in Water Body of Changshou Lake in Three Gorges Reservoir Region].

An investigation on the concentrations and the spatial distribution characteristics of different species of mercury in the water body of Changshou Lake in Three Gorges Reservoir region was carried out based on the AreGIS statistics module. The results showed that the concentration of the total mercury in Changshou Lake surface water ranged from 0.50 to 3.78 ng x L(-1), with an average of 1.51 ng x L(-1); the concentration of the total MeHg (methylmercury) ranged from 0.10 to 0.75 ng x L(-1), with an average of 0.23 ng x L(-1). The nugget effect value of total mercury in surface water (50.65%), dissolved mercury (49.80%), particulate mercury (29.94%) and the activity mercury (26.95%) were moderate spatial autocorrelation. It indicated that the autocorrelation was impacted by the intrinsic properties of sediments (such as parent materials and rocks, geological mineral and terrain), and on the other hand it was also disturbed by the exogenous input factors (such as aquaculture, industrial activities, farming etc). The nugget effect value of dissolved methylmercury (DMeHg) in Changshou lake surface water (3.49%) was less than 25%, showing significant strong spatial autocorrelation. The distribution was mainly controlled by environmental factors in water. The proportion of total MeHg in total Hg in Changshou Lake water reached 30% which was the maximum ratio of the total MeHg to total Hg in freshwater lakes and rivers. It implied that mercury was easily methylated in the environment of Chanashou Lake.

[Seasonal Variations in Vertical Profile of Hg Species and the Influential Factors in Changshou Reservior].

The vertical distribution of mercury (Hg) species were investigated in water and porewater of Changshou reservoir during the period from September 2013 to July 2014. Water samples were collected seasonally from five sampling sites, and the concentrations of Hg species were evaluated. Diffusion fluxes of Hg from sediment to overlaying water were also obtained. The results showed that the average concentrations of total Hg and total methylmercury (MeHg) were (14.77 ± 12.24) ng x L(-1) and (0.41 ± 0.47) ng x L(1), respectively. The concentrations of dissolved MeHg (DMeHg) was highest in 4-8 m under surface water, and then decreased with the increasing water depth with a subsequent increase in the bottom of Changshou Reservior. Peak particulate MeHg (PMeHg) values were found in 8-20 m under surface water, but not in the interface of sediment-water, suggesting that the increasing PMeHg might be related to the deposition of MeHg adsorbed to particulates from upper water. Two peak MeHg levels in pore water appeared in 16 and 28 cm under sediment surface, probably due to the extension of living region for sulfate reduction bacteria (SRB) to deeper sediment which resulted in increased methylation rate there. The diffusion fluxes of DMeHg from pore water to overlaying water were 28.2 ng x (m2 x d)(1) and 30.0 ng x (m2 x d)(-1) in autumn and summer, which were significantly higher than that in winter 3.8 ng x (m2 x d)(-1). It may be associated with the higher temperature in those two seasons. An obvious negative correlation was observed between DMeHg and dissolved oxygen (DO) in summer and spring (r = -0.482**, P < 0.05; r = -0.339, P < 0.01); however, similar correlations were not found in autumn and winter.