Telomere Length among Chinese Aged 75+ Years.

INTRODUCTION: Telomere length (TL) is generally regarded as a biomarker of aging. TL, which is influenced by sociodemographic factors, has been shown to be inversely associated with morbidity. However, most studies examined the youngest, and whether the findings can be extended to older individuals is less clear. Further, few studies have examined these questions in Chinese older adults. This cross-sectional study examined TL and its associated factors in Chinese aged 75+ years in Hong Kong. METHODS: Participants were from the Mr. and Ms. Osteoporosis cohort. A structured interview on sociodemographic factors and physical measurement was conducted. Frailty and sarcopenia status were respectively determined by Fried's criteria and the Asian Working Group for Sarcopenia definition. TL was measured by a molecular inversion probe-quantitative PCR assay and expressed as a novel telomere/a single copy reference gene (T/S) ratio. Adjusted binary logistic regressions were used to examine the associations between TL and the presence of multimorbidity, age-related diseases, frailty, and sarcopenia. RESULTS: Among 555 participants (mean age 83.6 ± 3.8 years, 41.3% females), the mean T/S ratio was 1.01 ± 0.20. Males had a lower T/S ratio (0.97 ± 0.20) compared with females (1.07 ± 0.18) (p < 0.001). A lower education level was related to a longer TL (p = 0.016). Being a current smoker was related to a shorter TL (p = 0.007). TL was not significantly different across categories of age, subjective socioeconomic status, drinking status, physical activity level, and body mass index (p > 0.05). There were no associations between TL and the presence of multimorbidity, diabetes, stroke, cardiovascular diseases, cognitive impairment, frailty, and sarcopenia. CONCLUSION: Among Chinese aged 75+ years, males had shorter TL compared with females. TL was not associated with age-related diseases, frailty, and sarcopenia in this age group. TL may not be a biological marker of aging among older individuals.

Interferon response and profiling of interferon response genes in peripheral blood of vaccine-naive COVID-19 patients.

Introduction: There is insufficient understanding on systemic interferon (IFN) responses during COVID-19 infection. Early reports indicated that interferon responses were suppressed by the coronavirus (SARS-CoV-2) and clinical trials of administration of various kinds of interferons had been disappointing. Expression of interferon-stimulated genes (ISGs) in peripheral blood (better known as interferon score) has been a well-established bioassay marker of systemic IFN responses in autoimmune diseases. Therefore, with archival samples of a cohort of COVID-19 patients collected before the availability of vaccination, we aimed to better understand this innate immune response by studying the IFN score and related ISGs expression in bulk and single cell RNAs sequencing expression datasets. Methods: In this study, we recruited 105 patients with COVID-19 and 30 healthy controls in Hong Kong. Clinical risk factors, disease course, and blood sampling times were recovered. Based on a set of five commonly used ISGs (IFIT1, IFIT2, IFI27, SIGLEC1, IFI44L), the IFN score was determined in blood leukocytes collected within 10 days after onset. The analysis was confined to those blood samples collected within 10 days after disease onset. Additional public datasets of bulk gene and single cell RNA sequencing of blood samples were used for the validation of IFN score results. Results: Compared to the healthy controls, we showed that ISGs expression and IFN score were significantly increased during the first 10 days after COVID infection in majority of patients (71%). Among those low IFN responders, they were more commonly asymptomatic patients (71% vs 25%). 22 patients did not mount an overall significant IFN response and were classified as low IFN responders (IFN score < 1). However, early IFN score or ISGs level was not a prognostic biomarker and could not predict subsequent disease severity. Both IFI27 and SIGLEC1 were monocyte-predominant expressing ISGs and IFI27 were activated even among those low IFN responders as defined by IFN score. In conclusion, a substantial IFN response was documented in this cohort of COVID-19 patients who experience a natural infection before the vaccination era. Like innate immunity towards other virus, the ISGs activation was observed largely during the early course of infection (before day 10). Single-cell RNA sequencing data suggested monocytes were the cell-type that primarily accounted for the activation of two highly responsive ISGs (IFI44L and IFI27). Discussion: As sampling time and age were two major confounders of ISG expression, they may account for contradicting observations among previous studies. On the other hand, the IFN score was not associated with the severity of the disease.

Peripheral Blood T Cell Gene Expression Responses to Exercise and HMB in Sarcopenia.

BACKGROUND: Sarcopenia is a major health problem in older adults. Exercise and nutrient supplementation have been shown to be effective interventions but there are limited studies to investigate their effects on the management of sarcopenia and its possible underlying mechanisms. Here, we studied T cell gene expression responses to interventions in sarcopenia. METHODS: The results of this study were part of a completed trial examining the effectiveness of a 12-week intervention with exercise and nutrition supplementation in community-dwelling Chinese older adults with sarcopenia, based on the available blood samples at baseline and 12 weeks from 46 randomized participants from three study groups, namely: exercise program alone (n = 11), combined-exercise program and nutrition supplement (n = 23), and waitlist control group (n = 12). T cell gene expression was evaluated, with emphasis on inflammation-related genes. Real-time PCR (RT-PCR) was performed on CD3 T cells in 38 selected genes. Correlation analysis was performed to relate the results of gene expression analysis with lower limb muscle strength performance, measured using leg extension tests. RESULTS: Our results showed a significant improvement in leg extension for both the exercise program alone and the combined groups (p < 0.001). Nine genes showed significant pre- and post-difference in gene expression over 12 weeks of intervention in the combined group. Seven genes (RASGRP1, BIN1, LEF1, ANXA6, IL-7R, LRRN3, and PRKCQ) showed an interaction effect between intervention and gene expression levels on leg extension in the confirmatory analysis, with confounder variables controlled and FDR correction. CONCLUSIONS: Our findings showed that T cell-specific inflammatory gene expression was changed significantly after 12 weeks of intervention with combined exercise and HMB supplementation in sarcopenia, and that this was associated with lower limb muscle strength performance.

Genome-Wide Search for SNP Interactions in GWAS Data: Algorithm, Feasibility, Replication Using Schizophrenia Datasets.

In this study, we looked for potential gene-gene interaction in susceptibility to schizophrenia by an exhaustive searching for SNP-SNP interactions in 3 GWAS datasets (phs000021:phg000013, phs000021:phg000014, phs000167) using our recently published algorithm. The search space for SNP-SNP interaction was confined to 8 biologically plausible ways of interaction under dominant-dominant or recessive-recessive modes. First, we performed our search of all pair-wise combination of 729,454 SNPs after filtering by SNP genotype quality. All possible pairwise interactions of any 2 SNPs (5 × 1011) were exhausted to search for significant interaction which was defined by p-value of chi-square tests. Nine out the top 10 interactions, protein coding genes were partnered with non-coding RNA (ncRNA) which suggested a new alternative insight into interaction biology other than the frequently sought-after protein-protein interaction. Therefore, we extended to look for replication among the top 10,000 interaction SNP pairs and high proportion of concurrent genes forming the interaction pairs were found. The results indicated that an enrichment of signals over noise was present in the top 10,000 interactions. Then, replications of SNP-SNP interaction were confirmed for 14 SNPs-pairs in both replication datasets. Biological insight was highlighted by a potential binding between FHIT (protein coding gene) and LINC00969 (lncRNA) which showed a replicable interaction between their SNPs. Both of them were reported to have expression in brain. Our study represented an early attempt of exhaustive interaction analysis of GWAS data which also yield replicated interaction and new insight into understanding of genetic interaction in schizophrenia.

Reference intervals of spot urine copper excretion in preschool children and potential application in pre-symptomatic screening of Wilson disease.

The objectives were to determine the reference intervals of spot urine copper excretion indexes in pre-school children and to evaluate their utility in screening for Wilson disease (WD). With spot urine collected from a control sample of preschool children (aged 3-7 years, n=153), the reference intervals of spot urine copper excretion indexes and their biological variation were defined. In order to investigate their utility performance in screening for WD in this age group, multiple spot urine samples from six WD patients who were diagnosed at presymptomatic stage were also analysed and compared. Cut-off values useful for detection of WD were defined by receiver operator curve (ROC) analysis. Biological (inter-individual) variation of spot urine copper indexes expressed as coefficient of variation (CVg) were around 60% at this age group, which was moderate and similar to other clinically useful urine tests, such as urine albumin excretion ratio. Spot urine copper excretion strongly correlated with both urine creatinine and osmolality. Linear regression against both creatinine and osmolality showed that ∼94% of data points in healthy preschool children fell within the prediction interval, suggesting that both were useful normalisation factors. ROC showed that copper to osmolality ratio was the best index with an area under curve (AUC) greater than 0.98. Cut-off values of 0.5 µmol/L, 0.1 µmol/mmol and 0.00085 µmol/mOsmol (32 µg/L, 56 µg/g creatinine and 0.054 µg/mOsmol, respectively, in conventional units) for spot urine copper concentration, copper to creatinine ratio and copper to osmolality ratio, respectively, have potential application in the differentiation of WD patients. Based on the data, a new WD screening strategy targeting preschool children is proposed. Application of a bivariate screening strategy using spot urine copper concentration and urine osmolality may be useful in a population-wide screening program for WD among preschool children.

Effect of CYP2D6 and CYP3A4 Genotypes on the Efficacy of Cholinesterase Inhibitors in Southern Chinese Patients With Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent form of dementia, and age is strongly associated with the incidence of AD. This study aimed to investigate the association between the genotypes of CYP2D6, CYP3A4, and CYP2C9 genes to the clinical efficacy and tolerability of cholinesterase inhibitors (ChEIs) in Chinese patients with AD. One hundred seventy-nine patients with AD with newly prescribed with ChEIs were recruited. The clinical response and tolerability were evaluated at baseline, 3rd-, 6th-, and 12th-month follow-ups and were compared according to their genotypes of CYP2D6, CYP3A4, and CYP2C9. Among patients prescribed with donepezil/galantamine, CYP2D6*10 carriers showed significantly less side effects (P = .009). CYP2D6*10 carriers responded better to ChEIs and resulted in better improvement in Alzheimer's Disease Assessment Scale-Cognitive subscale (P = .027) and Mini-Mental State Examination (P = .012). Further study is required to replicate the finding, and it might be useful for clinicians to decide the medication based on the patients' CYP genotypes.

Role of protein structure in variant annotation: structural insight of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency.

Genetic defects on 6-pyruvoyl-tetrahydropterin synthase (PTPS) are the most prevalent cause of hyperphenylalaninaemia not due to phenylalanine hydrolyase deficiency (phenylketonuria). PTPS catalyses the second step of tetrahydrobiopterin (BH4) cofactor biosynthesis, and its deficiency represents the most common form of BH4 deficiency. Untreated PTPS deficiency results in depletion of the neurotransmitters dopamine, catecholamine and serotonin causing neurological symptoms. We archived reported missense variants of the PTS gene. Common in silico algorithms were used to predict the effects of such variants, and substantial proportions (up to 19%) of the variants were falsely classified as benign or uncertain. We have determined the crystal structure of the human PTPS hexamer, allowing another level of interpretation to understand the potential deleterious consequences of the variants from a structural perspective. The in silico and structure approaches appear to be complimentary and may provide new insights that are not available from each alone. Information from the protein structure suggested that the variants affecting amino acid residues required for interaction between monomeric subunits of the PTPS hexamer were those misclassified as benign by in silico algorithms. Our findings illustrate the important utility of 3D protein structure in interpretation of variants and also current limitations of in silico prediction algorithms. However, software to analyse mutation in the perspective of 3D protein structure is far less readily available than other in silico prediction tools.

Revealing cellular and molecular transitions in neonatal germ cell differentiation using single cell RNA sequencing.

Neonatal germ cell development provides the foundation of spermatogenesis. However, a systematic understanding of this process is still limited. To resolve cellular and molecular heterogeneity in this process, we profiled single cell transcriptomes of undifferentiated germ cells from neonatal mouse testes and employed unbiased clustering and pseudotime ordering analysis to assign cells to distinct cell states in the developmental continuum. We defined the unique transcriptional programs underlying migratory capacity, resting cellular states and apoptosis regulation in transitional gonocytes. We also identified a subpopulation of primitive spermatogonia marked by CD87 (plasminogen activator, urokinase receptor), which exhibited a higher level of self-renewal gene expression and migration potential. We further revealed a differentiation-primed state within the undifferentiated compartment, in which elevated Oct4 expression correlates with lower expression of self-renewal pathway factors, higher Rarg expression, and enhanced retinoic acid responsiveness. Lastly, a knockdown experiment revealed the role of Oct4 in the regulation of gene expression related to the MAPK pathway and cell adhesion, which may contribute to stem cell differentiation. Our study thus provides novel insights into cellular and molecular regulation during early germ cell development.

Replication Study for the Association of GWAS-associated Loci With Adolescent Idiopathic Scoliosis Susceptibility and Curve Progression in a Chinese Population.

STUDY DESIGN: A genetic association (replication) study. OBJECTIVE: The aim of this study was to replicate and further evaluate the association among seven genome-wide association studies (GWAS)-identified single nucleotide polymorphisms (SNPs) in Chinese girls with adolescent idiopathic scoliosis (AIS) with disease onset, curve types, and progression. SUMMARY OF BACKGROUND DATA: AIS is the most common pediatric spinal deformity with a strong genetic predisposition. Recent GWAS identified 10 new disease predisposition loci for AIS. METHODS: Three hundred nineteen female AIS patients with Cobb angle ≥ 10 and 201 healthy controls were studied for the association with disease onset. Seven GWAS-identified SNPs (rs11190870 in LBX1, rs12946942 in SOX9/KCNJ2, rs13398147 in PAX3/EPH4, rs241215 in AJAP1, rs3904778 in BNC2, rs6570507 in GPR126, and rs678741 in LBX1-AS1) were analyzed. In subgroup analysis, AIS patients were subdivided by curve types and disease progression to examine for genotype association. RESULTS: We replicated the association with disease onset in four common SNPs rs11190870, rs3904778, rs6570507, and rs678741. In addition, rs1190870 and rs678741 remained significantly associated in the right thoracic curves only subgroup. However, no significant difference was observed with both clinical curve progression or Cobb angle. CONCLUSION: This study replicated the associations of four GWAS-associated SNPs with occurrence of AIS in our Chinese population. However, none of these SNPs was associated with curve severity and progression. The results suggest that curve progression may be determined by environmental (nongenetic) factor, but further study with a larger sample size is required to address this issue. LEVEL OF EVIDENCE: 4.

New Evidence Supporting the Role of FBN1 in the Development of Adolescent Idiopathic Scoliosis.

STUDY DESIGN: A genetic association study. OBJECTIVE: To determine whether common variants of fibrillin-1 (FBN1) and fibrillin-2 (FBN2) are associated with adolescent idiopathic scoliosis (AIS), and to further investigate to further investigate the functional role of FBN1 in the onset and progression of AIS. SUMMARY OF BACKGROUND DATA: Previous studies have identified several rare variants in FBN1 and FBN2 that were associated with AIS. There is, however, a lack of knowledge concerning the association between common variants of FBN1 and FBN2 and AIS. METHODS: Common variants covering FBN1 and FBN2 were genotyped in 952 patients with AIS and 1499 controls. Paraspinal muscles were collected from 66 patients with AIS and 18 patients with lumbar disc herniation (LDH) during surgical interventions. The differences of genotype and allele distributions between patients and controls were calculated using Chi-square test. The Student t test was used to compare the expression of FBN1 and FBN2 between patients with AIS and LDH. One-way analysis of variance test was used to compare the gene expression among different genotypes of the significantly associated variant. The Pearson correlation analysis was used to determine the relationship between FBN1 expression and the curve severity. RESULTS: The common variant rs12916536 of FBN1 was significantly associated with AIS. Patients were found to have significantly lower frequency of allele A than the controls (0.397 vs. 0.450, P = 1.10 × 10) with an odds ratio of 0.81. Moreover, patients with AIS were found to have significantly lower FBN1 expression than patients with LDH (0.00033 ±â€Š0.00015 vs. 0.00054 ±â€Š0.00031, P = 1.70 × 10). The expression level of FBN1 was remarkably correlated with the curve severity (r = -0.352, P = 0.02). There was no significant difference of FBN1 expression among different genotypes of rs12916536. CONCLUSION: Common variant of FBN1 is significantly associated with the susceptibility of AIS. Moreover, the decreased expression of FBN1 is significantly correlated with the curve severity of AIS. The functional role of FBN in AIS is worthy of further investigation. LEVEL OF EVIDENCE: 3.

Genetic susceptibility to Tuberculosis: Interaction between HLA-DQA1 and age of onset.

Several genome-wide association studies (GWAS) identified new single nucleotide polymorphisms (SNPs) with susceptibility to Tuberculosis (TB). However, many of them were not replicated across ethnic groups. The cause of this phenomenon of genetic heterogeneity is uncertain. Here, we attempted to replicate and evaluate the mechanism that causes genetic heterogeneity in several putative TB predisposition loci found by previous GWAS, including chromosome 18q, ASAP1, DUSP14, and HLA-DQA1. A Chinese cohort of 1200 TB patients and 1280 population controls were genotyped. The results showed that genetic predisposition to TB might operate in an age-specific manner. While no significant association was found in the whole samples, a SNP of HLA-DQA1, rs9272785, showed suggestive association within the young-onset TB subgroup (onset at 20-40 years of age, N = 396). The results provide support for the hypothesis that there are different pathogenesis mechanisms causing clinical TB disease in different age groups, and that genetics probably play a substantial role only in young-onset TB.

Comparative analysis of single-cell parallel sequencing approaches in oocyte application.

Single-cell parallel sequencing allows us to explore how genetic and epigenetic variations correlate of gene expression in the same cell. Beads-based approach and non-beads-based approach are the two present methods to separate DNA and RNA from the same cell. However, systematic difference between the two methods are lacking. In our study, we compared the performances of the two methods using transcriptome and methylome profiles generated simultaneously from single mouse oocytes. Our results showed that the beads-based approach could capture maximum quantity of mRNA but loss of DNA was inevitable, while the non-beads-based approach could obtain more DNA due to the undamaged nucleus obtained but at a cost of partial loss of mRNA. As the sequencing coverage of methylome sequencing in a single cell was relatively low, single-cell whole genome bisulfite sequencing (scWGBS) was preferable to generate the methylome map in single-cell parallel sequencing in comparison to single-cell reduced representation bisulfite sequencing (scRRBS). To the best of our knowledge, this is the first study to compare the two methods of single-cell parallel sequencing which offers a basic idea for deciding between the two methods and a direction of single-cell parallel sequencing development.

Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians.

Centenarians (CENs) are excellent subjects to study the mechanisms of human longevity and healthy aging. Here, we analyzed the transcriptomes of 76 centenarians, 54 centenarian-children, and 41 spouses of centenarian-children by RNA sequencing and found that, among the significantly differentially expressed genes (SDEGs) exhibited by CENs, the autophagy-lysosomal pathway is significantly up-regulated. Overexpression of several genes from this pathway, CTSB, ATP6V0C, ATG4D, and WIPI1, could promote autophagy and delay senescence in cultured IMR-90 cells, while overexpression of the Drosophila homolog of WIPI1, Atg18a, extended the life span in transgenic flies. Interestingly, the enhanced autophagy-lysosomal activity could be partially passed on to their offspring, as manifested by their higher levels of both autophagy-encoding genes and serum beclin 1 (BECN1). In light of the normal age-related decline of autophagy-lysosomal functions, these findings provide a compelling explanation for achieving longevity in, at least, female CENs, given the gender bias in our collected samples, and suggest that the enhanced waste-cleaning activity via autophagy may serve as a conserved mechanism to prolong the life span from Drosophila to humans.

Genetic Variant of PAX1 Gene Is Functionally Associated With Adolescent Idiopathic Scoliosis in the Chinese Population.

STUDY DESIGN: A genetic association study. OBJECTIVE: To investigate the association between PAX1 gene and the susceptibility of adolescent idiopathic scoliosis (AIS) in the Chinese population and to further determine the functional variant regulating PAX1 expression in patients with AIS. SUMMARY OF BACKGROUND DATA: In a previous study an enhancer locus of PAX1 was reported to be associated with the development of AIS in the Caucasian and the Japanese population. However, there is a paucity of knowledge concerning the functional role of PAX1 in the Chinese AIS population. METHODS: The single-nucleotide polymorphisms rs6137473 and rs169311 were genotyped in 2914 patients and 3924 controls. The differences of genotype and allele distributions between patients and controls were calculated using chi-square test. Paraspinal muscles were collected from 84 patients with AIS. The one-way analysis of variance test was used to compare the mRNA expression of PAX1 among different genotypes. RESULTS: Both rs6137473 and rs169311 were significantly associated with the susceptibility of AIS. Allele G of rs6137473 and allele A of rs169311 can significantly add to the risk of AIS with an odds ratio of 1.17 and 1.22, respectively. Moreover, there was significant difference regarding the expression of the PAX1 between the concave side and convex side of the patients. Patients with genotype AA of rs169311 had significantly decreased expression of PAX1 than those with genotype CC. As for rs6137473, no remarkable difference of PAX1 expression was found among the three genotypes. CONCLUSION: The association between PAX1 and the susceptibility of AIS was successfully replicated in the Chinese population. Moreover, rs169311 could be a functional variant regulating the expression of PAX1 in the paraspinal muscles of AIS. Further functional analysis is warranted for a comprehensive knowledge on the contribution of this variant to the development of AIS. LEVEL OF EVIDENCE: 3.

VCNet: vector-based gene co-expression network construction and its application to RNA-seq data.

MOTIVATION: Building gene co-expression network (GCN) from gene expression data is an important field of bioinformatic research. Nowadays, RNA-seq data provides high dimensional information to quantify gene expressions in term of read counts for individual exons of genes. Such an increase in the dimension of expression data during the transition from microarray to RNA-seq era made many previous co-expression analysis algorithms based on simple univariate correlation no longer applicable. Recently, two vector-based methods, SpliceNet and RNASeqNet, have been proposed to build GCN. However, they failed to work when sample size is less than the number of exons. RESULTS: We develop an algorithm called VCNet to construct GCN from RNA-seq data to overcome this dimensional problem. VCNet performs a new statistical hypothesis test based on the correlation matrix of a gene-gene pair using the Frobenius norm. The asymptotic distribution of the new test is obtained under the null model. Simulation studies demonstrate that VCNet outperforms SpliceNet and RNASeqNet for detecting edges of GCN. We also apply VCNet to two expression datasets from TCGA database: the normal breast tissue and kidney tumour tissue, and the results show that the GCNs constructed by VCNet contain more biologically meaningful interactions than existing methods. CONCLUSION: VCNet is a useful tool to construct co-expression network. AVAILABILITY AND IMPLEMENTATION: VCNet is open source and freely available from https://github.com/wangzengmiao/VCNet under GNU LGPL v3. CONTACT: dengmh@pku.edu.cn or nelsontang@cuhk.edu.hk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genetic variant of BNC2 gene is functionally associated with adolescent idiopathic scoliosis in Chinese population.

Adolescent idiopathic scoliosis (AIS) is a structural curvature of the spine that was estimated to affect millions of children worldwide. Recent study shows that the functional variant rs10738445 could add to the risk of AIS through the regulation of BNC2 gene. This study aims to investigate whether the rs10738445 of BNC2 gene is a functional susceptible locus for AIS in the Chinese population and to further clarify the association of the BNC2 expression with the curve severity. SNP rs10738445 was genotyped in 1952 patients and 2492 controls, and further replicated in 693 patients and 254 controls. We found that patients have a significantly higher frequency of CC than the controls (21.9 vs. 17.7%, p = 0.004 for stage 1; 12.6 vs. 7.9%, p = 0.03 for stage 2). Allele C can significantly add to the risk of AIS with an OR of 1.14-1.24. AIS patients were found to have significantly higher BNC2 expression than the controls. The BNC2 expression was significantly correlated with the curve severity (r = 0.316, p = 0.02). In conclusion, our study suggests a functional role of BNC2 in the development and progression of the spinal deformity in AIS.

Association of gene expression and methylation of UQCRC1 to the predisposition of Alzheimer's disease in a Chinese population.

DNA methylation is an important epigenetic mechanism for gene regulation and it is well established there is association between aging and DNA methylation. Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by amyloid plaque deposition and formation of neurofibrillary tangles. In this study, we examined the correlation between DNA methylation and gene expression of seven genes including CTSB, CTSD, DDT, TSC1, NRD1, UQCRC1 and NDUFA6 and its effect on the risk of AD in a Chinese population. Our finding showed significantly increased gene expression of these 7 genes in AD patients (2.7-fold-8.6-fold). UQCRC1 was highly methylated in AD patients and there was strong positive correlation between gene expression level and methylation status of UQCRC1 (p < 0.001). Further analysis showed the methylation status of UQCRC1 was significantly associated with gene expression of NRD1, DDT, CTSB and CTSD, suggested the regulatory mechanism on these 4 genes by UQCRC1. Our study further suggested the role of methylation in gene regulation and the role in AD.

Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls.

Adolescent idiopathic scoliosis (AIS) is a structural deformity of the spine affecting millions of children. As a complex disease, the genetic aetiology of AIS remains obscure. Here we report the results of a four-stage genome-wide association study (GWAS) conducted in a sample of 4,317 AIS patients and 6,016 controls. Overall, we identify three new susceptibility loci at 1p36.32 near AJAP1 (rs241215, Pcombined=2.95 × 10(-9)), 2q36.1 between PAX3 and EPHA4 (rs13398147, Pcombined=7.59 × 10(-13)) and 18q21.33 near BCL-2 (rs4940576, Pcombined=2.22 × 10(-12)). In addition, we refine a previously reported region associated with AIS at 10q24.32 (rs678741, Pcombined=9.68 × 10(-37)), which suggests LBX1AS1, encoding an antisense transcript of LBX1, might be a functional variant of AIS. This is the first GWAS investigating genetic variants associated with AIS in Chinese population, and the findings provide new insight into the multiple aetiological mechanisms of AIS.

Dynamic changes of DNA epigenetic marks in mouse oocytes during natural and accelerated aging.

Aging is a complex time-dependent biological process that takes place in every cell and organ, eventually leading to degenerative changes that affect normal biological functions. In the past decades, the number of older parents has increased significantly. While it is widely recognized that oocyte aging poses higher birth and reproductive risk, the exact molecular mechanisms remain largely elusive. DNA methylation of 5-cytosine (5mC) and histone modifications are among the key epigenetic mechanisms involved in critical developmental processes and have been linked to aging. However, the impact of oocyte aging on DNA demethylation pathways has not been examined. The recent discovery of Ten-Eleven-Translocation (TET) family proteins, thymine DNA glycosylase (TDG) and the demethylation intermediates 5hmC, 5fC and 5caC has provided novel clues to delineate the molecular mechanisms in DNA demethylation. In this study, we examined the cellular level of modified cytosines (5mC, 5hmC, 5fC and 5caC) and Tet/Tdg expression in oocytes obtained from natural and accelerated oocyte aging conditions. Here we show all the DNA demethylation marks are dynamically regulated in both aging conditions, which are associated with Tet3 over-expression and Tdg repression. Such an aberrant expression pattern was more profound in accelerated aging condition. The results suggest that DNA demethylation may be actively involved in oocyte aging and have implications for development of potential drug targets to rejuvenate aging oocytes. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.