Molecular characterization of mutations associated with resistance among 72 multidrug-resistant strains of Mycobacterium tuberculosis by whole genome sequencing / 中国热带医学

@#Abstract: Objective　To understand the characteristics of mutations associated with resistance among 72 multidrug-resistant tuberculosis (MDR-TB) strains using whole genome sequencing (WGS) and to evaluate the performance of WGS for predicting MDR-TB drug resistance. Methods　The clinical strains isolated from patients who visited the outpatient department of Tianjin Center for Tuberculosis Control from January to September in 2020 were collected. Identification tests using p-nitrobenzoic acid (PNB) medium were performed. Drug susceptibility tests (proportion method) on L-J medium were performed. After excluding duplicate strains, 72 MDR-TB strains were selected for WGS. Data were analyzed by using online databases and the phenotypic drug susceptibility test results were compared with resistance profiles predicted by WGS. Results　All of 72 MDR-TB strains belonged to linage 2, and there was no significant difference in rate of pre-extensive drug-resistant tuberculosis (pre-XDR-TB) between modern type and ancestral type (χ2=0.287, P=0.592). A total of 81 mutation types were found from resistance-related genes for 12 anti-tuberculosis drugs, and the common mutation types in different drug-resistant strains were: streptomycin (SM): rpsL Lys43Arg; isoniazid (INH): katG Ser315Thr; rifampicin (RIF): rpoB Ser450Leu; ethambutol (EMB): embB Met306Val; ofloxacin (OFX), levofloxacin (LFX), moxifloxacin (MFX): gyrA Asp94Gly; kanamycin (KAM), capreomycin (CAP), amikacin (AMK): rrs 1401a>g; para-aminosalicylic acid (PAS): folC Ile43Thr. Nine mutation types were found in 9 prothionamide (PTO)-resistant strains, one type for each strain. The sensitivity and specificity of WGS for predicting resistance to different drugs were SM: 98.15% and 88.89%, INH: 90.28% and -, RIF: 98.62% and -, EMB: 79.49% and75.76%, OFX: 97.30% and 85.71%, KAM: 85.71% and 98.46%, PAS: 27.27% and 95.08%, PTO: 81.82% and 60.66%, CAP: 60.00% and 98.51%, LFX: 97.22% and 83.33%, MFX: 97.30% and 85.71%, AMK:100.00% and 100.00%, respectively. Conclusion　WGS is a rapid and promising method which has high consistency with the phenotypic drug sensitivity test. Therefore, it has good application prospects in predicting drug resistance in MDR-TB.

How data science and AI-based technologies impact genomics

Advancements in high-throughput sequencing have yielded vast amounts of genomic data, which are studied using genome-wide association study (GWAS)/phenome-wide association study (PheWAS) methods to identify associations between the genotype and phenotype. The associated findings have contributed to pharmacogenomics and improved clinical decision support at the point of care in many healthcare systems. However, the accumulation of genomic data from sequencing and clinical data from electronic health records (EHRs) poses significant challenges for data scientists. Following the rise of artificial intelligence (AI) technology such as machine learning and deep learning, an increasing number of GWAS/PheWAS studies have successfully leveraged this technology to overcome the aforementioned challenges. In this review, we focus on the application of data science and AI technology in three areas, including risk prediction and identification of causal single-nucleotide polymorphisms, EHR-based phenotyping and CRISPR guide RNA design. Additionally, we highlight a few emerging AI technologies, such as transfer learning and multi-view learning, which will or have started to benefit genomic studies.

Association between exonic polymorphisms of human leukocyte antigen-G gene and non-segmental vitiligo in the Korean population

Background: Vitiligo is a pigmentary skin disorder characterised by a chronic and progressive loss of melanocytes. Although several theories have been suggested to the pathogenesis of vitiligo, an autoimmune process leading to melanocyte destruction appears most likely. Human leukocyte antigen-G is a non-classic, major histocompatibility complex Class I molecule that plays an important role in the suppression of the immune response. Several recent studies have provided evidences that polymorphisms in the human leukocyte antigen-G gene might be related with autoimmune diseases. Objectives: The aim of this study was to decide whether exonic single nucleotide polymorphisms in human leukocyte antigen-G contribute to the risk of developing non-segmental vitiligo in the Korean population. Methods: To evaluate the associations between exonic single nucleotide polymorphisms (rs1630223 [Ala5Ala] and rs12722477 [Leu134Ile]) of human leukocyte antigen-G and vitiligo, 244 patients with vitiligo and 398 healthy controls were recruited. Genotyping was performed using Fluidigm 192.24 Dynamic Array with EP1 (Fluidigm Corp., CA). The SNP type assay (Fluidigm Corp., CA), which employs allele-specifically designed fluorescences (FAM or VIC) primers and a common reverse primer was applied and the data were analysed using the EP1 single nucleotide polymorphisms genotyping analysis software to obtain genotype calls. Results: Two exonic single nucleotide polymorphisms (rs1630223 and rs12722477) exhibited significant associations with susceptibility and remained a statistically significant association following Bonferroni correction. These two single nucleotide polymorphisms were located within a block of linkage disequilibrium. Haplotypes G-C and A-A comprising rs1630223 and rs12722477 demonstrated a significant association with non-segmental vitiligo. Limitations: The protein expression level of patients with vitiligo and controls was not studied and a replication study of the genetic association in an independent group was not managed. Conclusion: Our results suggest that exonic human leukocyte antigen-G polymorphisms (rs1630223 and rs12722477) are associated with the development of non-segmental vitiligo.

Progress in genetic epidemiology of gestational diabetes mellitus / 中华围产医学杂志

Gestational diabetes mellitus poses a substantial threat to the short- and long-term health of women and their offspring. Previous studies have identified a number of genetic risk factors for gestational diabetes through candidate gene strategy and whole genome studies. Many of these identified genetic variations have also been proved to be associated with type 2 diabetes, abnormal glycometabolism as well as insulin secretion and resistance. This article reviews the recent progress in the genetic epidemiology of gestational diabetes mellitus.

Genetic studies of primary biliary cholangitis in the post-GWAS era / 临床肝胆病杂志

With the constant increase in the awareness of primary biliary cholangitis (PBC) and the continuous improvement in related diagnostic methods in the past two decades, the incidence and prevalence rates of PBC tend to increase and PBC is now the most common autoimmune liver disease worldwide. A series of family-based studies in the early stage have shown that PBC has strong genetic tendency, and subsequent genomic analyses have been performed for PBC in different populations and have obtained a large amount of genetic data. Future genetic studies of PBC will focus on translating these results into clinical practice.

Modelos multivariados en la búsqueda de regiones genómicas para resistencia a mal de río cuarto y bacteriosis en maíz / Multi-trait models for genomic regions associated with mal de río cuarto and bacterial disease in maize

RESUMEN La producción de maíz (Zea Mays L.) ha sido ampliamente beneficiada con la mejora de líneas endocriadas respecto a la resistencia a enfermedades causadas por virus y hongos. Sin embargo, es notable la ausencia de genotipos resistentes a bacteriosis. El objetivo del presente estudio fue identificar regiones genómicas para la mejora de resistencia a Mal de Río Cuarto (MRC) y a bacteriosis (BD) en un germoplasma diverso de maíz. Se evaluó, para ambas enfermedades, una población diversa de líneas de maíz en el ciclo de cultivo 2019-2020 en la región argentina donde la virosis MRC es endémica. Se estimó incidencia y severidad de MRC y BD en cada línea y se realizó un estudio de mapeo por asociación (GWAS) con 78.376 marcadores SNPs. Un modelo multicarácter se utilizó para evaluar simultáneamente la resistencia a MRC y BD en las líneas evaluadas. El germoplasma evidenció alta variabilidad genética tanto para la mejora de la resistencia a MRC como a BD, pero no se observó correlación genética significativa entre la respuesta a ambas enfermedades. Se identificaron regiones genómicas promisorias para resistencia a MRC y a BD, que serán confirmadas en evaluaciones en nuevos ambientes.

ABSTRACT Maize (Zea Mays L.) production has been greatly benefited from the improvement of inbred lines in regard to the resistance to diseases. However, the absence of resistant genotypes to bacteriosis is remarkable. The aim of the study was to identify genomic regions for resistance to Mal de Río Cuarto (MRC) and to bacterial disease (BD) in a diverse maize germplasm evaluated in the Argentinian region where MRC virus is endemic. A maize diverse population was assessed for both diseases during the 2019-2020 crop season. Incidence and severity of MRC and BD were estimated for each line and a genome wide association study (GWAS) was conducted with 78,376 SNP markers. A multi-trait mixed linear model was used for simultaneous evaluation of resistance to MRC and BD in the scored lines. The germplasm showed high genetic variability for both MRC and BD resistance. No significant genetic correlation was observed between the response to both diseases. Promising genomic regions for resistance to MRC and BD were identified and will be confirmed in further trials.

Polymorphism of urate transporter in gout and its correlation with gout treatment / 中国组织工程研究

BACKGROUND: Urate transporters such as GLUT9, URAT1, NPT1 and ABCG2 are directly involved in the regulation of human serum uric acid levels. The gene polymorphism of urate transporter is closely related to the occurrence and development of gout. Therefore, the targeted therapy of urate transporter is a new way to treat gout. OBJECTIVE: To summarize the research progress of polymorphism expression of urate transporter in gout and its correlation with clinical drugs in recent years, therefore providing literature and theoretical basis for further exploration of personalized treatment of gout and hyperuricemia. METHODS: The first author searched CNKI, WanFang database and PubMed database. The key words were “Gout, Urate transporter, Hyperuricemia, Polymorphism, GWAS, Therapy” in Chinese and English, respectively. Totally 131 literatures were retrieved. According to the inclusion and exclusion criteria, 78 articles regarding the genetic polymorphism of urate transporter in gout and the correlation between the mechanism of action of gout drugs and urate transporter were screened out and summarized. RESULTS AND CONCLUSION: A large number of studies have shown that urate transporter polymorphism is closely related to uric acid homeostasis, with GLUT9, URAT1, NPT1 and ABCG2 being the most important. These proteins are differentially expressed in different populations and are closely related to the reaction mechanism of gout drugs. In the future diagnosis and treatment, the results of these studies can help assess the need for treatment in patients with hyperuricemia, and help patients with gout formulate personalized and effective treatment plans. It may be a feasible solution to treat hyperuricemia by activating BCRP to enhance the clearance of uric acid in the intestine.

Genome-wide association analysis reveals regulation of at-risk loci by DNA methylation in prostate cancer / 亚洲男科学杂志(英文版)

Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations. Prostate cancer (PCa) is characterized by variable clinical manifestations and frequently unpredictable outcomes. We performed an expression quantitative trait loci (eQTL) analysis to identify the genomic regions that regulate gene expression in PCa and identified a relationship between DNA methylation and clinical information. Using multi-level information published in The Cancer Genome Atlas, we performed eQTL-based analyses on DNA methylation and gene expression. To better interpret these data, we correlated loci and clinical indexes to identify the important loci for both PCa development and progression. Our data demonstrated that although only a small proportion of genes are regulated via DNA methylation in PCa, these genes are enriched in important cancer-related groups. In addition, single nucleotide polymorphism analysis identified the locations of CpG sites and genes within at-risk loci, including the 19q13.2-q13.43 and 16q22.2-q23.1 loci. Further, an epigenetic association study of clinical indexes detected risk loci and pyrosequencing for site validation. Although DNA methylation-regulated genes across PCa samples are a small proportion, the associated genes play important roles in PCa carcinogenesis.

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma / 医学前沿

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Alelos asociados al índice de severidad de la enfermedad Mal de Río Cuarto en germoplasma exótico de maíz / Alleles associated to disease severity index of Mal de Río Cuarto disease in maize exotic germplasm

RESUMEN El Mal de Río Cuarto (MRC) es una de las enfermedades virales más importantes del maíz en Argentina. El índice de severidad de enfermedad (ISE) permite combinar la incidencia y la severidad de una enfermedad en una métrica única. La reacción genotípica a MRC ha sido muy estudiada en poblaciones biparentales, sin embargo este carácter complejo no se ha analizado mediante estudios de mapeo por asociación. El objetivo del presente trabajo es identificar nuevos alelos de resistencia asociados con el ISE de la enfermedad MRC de maíz en un germoplasma exótico del Centro Internacional de Mejoramiento de Maíz y Trigo (CIMMYT). Una población de líneas de maíz del CIMMYT se evaluó fenotípicamente en ambientes donde la enfermedad es endémica. Los predictores del efecto genotípico (BLUP, best linear unbiased predictor) del ISE de MRC y 78.376 marcadores SNP (Single Nucleotide Polymorphism) se usaron para realizar el mapeo por asociación en 186 líneas de maíz. Los componentes de varianza y los valores de heredabilidad sugieren una amplia variabilidad genotípica en la población de líneas. El mapeo por asociación permitió identificar 11 posibles QTL de resistencia a MRC. La incorporación de germoplasma exótico en los programas de mejoramiento de maíz locales podría contribuir favorablemente a la creación de genotipos híbridos con mayor nivel de resistencia a MRC. La capacidad predictiva de los marcadores asociados con la resistencia a MRC indican que la selección asistida por marcadores es una herramienta recomendable para seleccionar genotipos resistentes a MRC.

ABSTRACT Mal de Río Cuarto (MRC) is one of the most important viral diseases of maize in Argentina. The disease severity index (DSI) allows to combine the incidence and severity of a disease in a single metric. The genotypic reaction to MRC has been extensively studied in biparental populations. However, this complex trait has not been analyzed by genome-wide association studies (GWAS). The aim of this work is to identify new resistance alleles associated with DSI of MRC in an exotic germplasm from the International Maize and Wheat Improvement Center (CIMMYT). A population of maize lines from CIMMYT was phenotypically evaluated in environments in the area where the disease is endemic. The predictors of genetic effects (BLUP, best linear unbiased predictor) and 78,376 SNP markers (Single Nucleotide Polymorphism) were used to perform the GWAS in 186 maize lines. The values of variance components and mean-basis heritability suggest a wide genotypic variability in the population. The GWAS allowed to identify 11 putative QTL of resistance to MRC. The incorporation of exotic germplasm into local maize breeding programs could contribute favorably to the creation of hybrids with a higher level of resistance to MRC. The predictive ability of associated markers with MRC resistance indicates that marker-assisted selection is an advisable tool for selecting MRC resistant genotypes.

Research progress of GWAS in hyperuricemia / 公共卫生与预防医学

Hyperuricemia is a chronic disease caused by the imbalance of uric acid synthesis and excretion, which is influenced by both environmental and genetic factors. The results of genome-wide association analysis related to hyperuricemia in different regions during the past decade have shown that genes related to hyperuricemia may be region- specific. This article summarizes the genes detected by GWAS, and describes some of the involved molecular mechanisms. The genes related to hyperuricemia shared by people in Europe, Asia, Africa and South America, and genes related to hyperuricemia unique to Asian populations are reviewed in this article. In addition, some of the genes’ functions are discussed to enhance the understanding of the pathogenesis of hyperuricemia.

Genetic Architecture of Circulating Very-Long-Chain (C24:0 and C22:0) Ceramide Concentrations

OBJECTIVE: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations.METHODS: Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment.RESULTS: The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; p=1.8E-9) and 0.25 (SE, 0.08; p=0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C22:0 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (p=2.83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 ceramide concentrations (p=9.94E-09).CONCLUSION: SNPs near the SPTLC3 gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of de novo sphingolipid synthesis) were associated with plasma C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.

Assessment of the Clinical Heterogeneity of Kawasaki Disease Using Genetic Variants of BLK and FCGR2A

BACKGROUND AND OBJECTIVES: Patients with Kawasaki disease (KD) are clinically heterogeneous because its diagnosis is based solely on clinical observation and there are no definitive biomarkers. We dissected the clinical heterogeneity of KD patients using the KD-associated genetic variants. METHODS: We performed a genetic association analysis in several KD subgroups categorized by clinical characteristics using the KD-associated variants of the B lymphoid tyrosine kinase (BLK; rs6993775) and Fc gamma receptor II a (FCGR2A; rs1801274) in a large number of case (n=1,011) and control (n=4,533) samples. RESULTS: BLK and FCGR2A were very significantly associated with KD in Korean KD patients (odds ratio [OR],1.48; p=4.63×10⁻¹¹ for BLK, and OR, 1.26; p=1.42×10⁻⁴ for FCGR2A). However, in KD subgroup analysis, we found that neither BLK nor FCGR2A were associated with either incomplete Kawasaki disease (iKD) type patients or those older than 5 years of age (p>0.2), suggesting that patients with iKD or those older than 5 years of age are a unique subgroup of KD. In genetic association analysis after excluding iKD patients and those older than 5 years old, we found that BLK was associated with all KD subgroups, whereas FCGR2A was specifically associated with male KD patients younger than 1 year of age (OR, 2.22; p=2.35×10⁻⁵). CONCLUSIONS: KD is a clinically and genetically heterogeneous disease. These findings will provide new insights into the clinical and genetic heterogeneity of KD.

Analysis of differences in human leukocyte antigen between the two Wellcome Trust Case Control Consortium control datasets

The Wellcome Trust Case Control Consortium (WTCCC) study was a large genome-wide association study that aimed to identify common variants associated with seven diseases. That study combined two control datasets (58C and UK Blood Services) as shared controls. Prior to using the combined controls, the WTCCC performed analyses to show that the genomic content of the control datasets was not significantly different. Recently, the analysis of human leukocyte antigen (HLA) genes has become prevalent due to the development of HLA imputation technology. In this project, we extended the between-control homogeneity analysis of the WTCCC to HLA. We imputed HLA information in the WTCCC control dataset and showed that the HLA content was not significantly different between the two control datasets, suggesting that the combined controls can be used as controls for HLA fine-mapping analysis based on HLA imputation.

In silico approach to calculate the transcript capacity

We sought the novel concept, transcript capacity (TC) and analyzed TC. Our approach to estimate TC was through an in silico method. TC refers to the capacity that a transcript exerts in a cell as enzyme or protein function after translation. We used the genome-wide association study (GWAS) beta effect and transcription level in RNA-sequencing to estimate TC. The trait was body fat percent and the transcript reads were obtained from the human protein atlas. The assumption was that the GWAS beta effect is the gene’s effect and TC was related to the corresponding gene effect and transcript reads. Further, we surveyed gene ontology (GO) in the highest TC and the lowest TC genes. The most frequent GOs with the highest TC were neuronal-related and cell projection organization related. The most frequent GOs with the lowest TC were wound-healing related and embryo development related. We expect that our analysis contributes to estimating TC in the diverse species and playing a benevolent role to the new bioinformatic analysis.

Genome-Wide Association of Genetic Variation in the PSCA Gene with Gastric Cancer Susceptibility in a Korean Population / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Half of the world's gastric cancer cases and the highest gastric cancer mortality rates are observed in Eastern Asia. Although several genome-wide association studies (GWASs) have revealed susceptibility genes associated with gastric cancer, no GWASs have been conducted in the Korean population, which has the highest incidence of gastric cancer. MATERIALS AND METHODS: We performed genome scanning of 450 gastric cancer cases and 1,134 controls via Affymetrix Axiom Exome 319 arrays, followed by replication of 803 gastric cancer cases and 3,693 healthy controls. RESULTS: We showed that the rs2976394 in the prostate stem cell antigen (PSCA) gene is a gastriccancer-susceptibility gene in a Korean population, with genome-wide significance and an odds ratio (OR) of 0.70 (95% confidence interval [CI], 0.64 to 0.77). A strong linkage disequilibrium with rs2294008 was also found, indicating an association with susceptibility. Individuals with the CC genotype of the PSCA gene showed an approximately 2-fold lower risk of gastric cancer compared to those with the TT genotype (OR, 0.47; 95% CI, 0.39 to 0.57). The effect of the PSCA gene on gastric cancer was more prominent in the female population and for diffuse type gastric cancer. CONCLUSION: Our result confirmed that the PSCA gene may be the most important susceptibility gene for gastric cancer risk in a Korean population.

Genome-wide association study of degenerative mitral valve disease in Maltese dogs

Genome-wide association study (GWAS) is a powerful tool for identifying the genetic causes of various diseases. This study was conducted to identify genomic variation in Maltese dog genomes associated with degenerative mitral valve disease (DMVD) development and to evaluate the association of each biological condition with DMVD in Maltese dogs. DNA was extracted from blood samples obtained from 48 Maltese dogs (32 with DMVD and 16 controls). Genome-wide single nucleotide polymorphism (SNP) genotyping was performed. The top 30 SNPs from each association of various conditions and genetic variations were mapped to their gene locations. A total of 173,662 loci were successfully genotyped, with an overall genotype completion rate of 99.41%. Quality control analysis excluded 46,610 of these SNPs. Manhattan plots were produced using allelic tests with various candidate clinical conditions. A significant peak of association was observed between mitral valve prolapse (MVP) and SNPs on chromosome 17. The present study revealed significant SNPs in several genes associated with cardiac function, including PDZ2, Armadillo repeat protein detected in velo-cardio-facial syndrome, catenin (cadherin-associated protein) alpha 3, low-density lipoprotein receptor class A domain containing protein 4, and sterile alpha motif domain containing protein 3. To our knowledge, this is the first study of a genetic predisposition to DMVD in Maltese dogs. Although only a limited number of cases were analyzed, these data could be the basis for further research on the genetic predisposition to MVP and DMVD in Maltese dogs.

Genetic regulation of linear growth

Linear growth occurs at the growth plate. Therefore, genetic defects that interfere with the normal function of the growth plate can cause linear growth disorders. Many genetic causes of growth disorders have already been identified in humans. However, recent genome-wide approaches have broadened our knowledge of the mechanisms of linear growth, not only providing novel monogenic causes of growth disorders but also revealing single nucleotide polymorphisms in genes that affect height in the general population. The genes identified as causative of linear growth disorders are heterogeneous, playing a role in various growth-regulating mechanisms including those involving the extracellular matrix, intracellular signaling, paracrine signaling, endocrine signaling, and epigenetic regulation. Understanding the underlying genetic defects in linear growth is important for clinicians and researchers in order to provide proper diagnoses, management, and genetic counseling, as well as to develop better treatment approaches for children with growth disorders.

Application values of genome-wide association studies in screening for breast cancer / 中华流行病学杂志

Objective@#To investigate the potential application values of screening on breast cancer, using the single-nucleotide polymorphisms (SNPs) that were identified from the genome- wide association studies (GWASs).@*Methods@#Two million Chinese women aged 35-69 years were simulated, based on both age distributions, age-specific incidence rates of breast cancer and the distribution of known risk factors, in 2013. Twenty-three SNPs identified from GWAS were further simulated. Both genetic-related risks explained by each SNPs and the improvement on the risks under reclassification, were used to select SNPs for the prediction on breast cancer among the targeted high-risk population. Further analyses were conducted to investigate the following items as: improvements on detection rates of breast cancer among the high-risk populations, areas under the curve (AUC) and the odds ratio (OR) among women at high risk.@*Results@#A total of 12 SNPs were eligible for targeting the high-risk population of breast cancer. When high-risk populations were defined as women whose predicted risks were higher than the 95th predicted risk of the whole population, the detection rate (146.99/100 000) among high-risked women predicted by 12 SNPs would be significantly lower than 177.46/100 000, which was predicted by the known risk factors (P<0.001), among the high-risked women. Among those women at high risk, the detection rate (229.00/100 000) predicted by integrating known risk factors and 12 SNPs was significantly higher than that predicted by known risk factors (P<0.001). Also, the AUC increased from 64.4% to 67.8% (P<0.001), and the OR of increased from 3.32 to 4.33, predicted by integrating known risk factors and 12 SNPs, for women at high risk on breast cancer.@*Conclusion@#Targeted SNPs that were identified from genome- wide association studies could be used to improve the detection rates as well as the overall accuracy of risk prediction so as to identify the potential high-risk women on breast cancer before carrying on the screening program.

Application of polygenic risk scores in risk prediction and precision prevention of complex diseases: opportunities and challenges / 中华流行病学杂志

Along with the rapid progress in the field of human genomics, genome-wide association studies have successfully identified numerous risk loci for complex diseases. Polygenic risk scores can predict disease risk by integrating the effects of multiple susceptibility loci, and begin to show good performance for improving risk prediction, screening strategy and precision prevention. This paper briefly reviews the recent progress of polygenic risk scores in disease prevention, and summarizes the opportunities and challenges of its application.