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Advancement in genetic variants conferring obesity susceptibility from genome-wide association studies

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Frontiers of Medicine 2015年第2期9卷 146-161页

作者： Tao Wang Weiping Jia Cheng Hu Shanghai Diabetes Institute Shanghai Key Laboratory of Diabetes Mellitus Shanghai Clinical Center for Diabetes Shanghai Jiao TongUniversity Affiliated Sixth People's Hospital Shanghai 200233 China

Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies （GWAS） has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene （FTO）, but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.

关键词： obesity genetics genome-wide association studies body mass index fat mass- and obesity-associated gene

SNPTransformer:A Lightweight Toolkit for genome-wide association studies

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Genomics, Proteomics & Bioinformatics 2010年第4期8卷 268-273页

作者： Changzheng Dong School of Medicine Ningbo University Ningbo 315211 China

High-throughput genotyping chips have produced huge datasets for genome-wide association studies （GWAS） that have contributed greatly to discovering susceptibility genes for complex diseases. There are two strategies for performing data analysis for GWAS. One strategy is to use open-source or commercial packages that are designed for GWAS. The other is to take advantage of classic genetic programs with specific functions, such as linkage disequilibrium mapping, haplotype inference and transmission disequilibrium tests. However, most classic programs that are available are not suitable for analyzing chip data directly and require custom-made input, which results in the inconvenience of converting raw genotyping files into various data formats. We developed a powerful, user-friendly, lightweight program named SNPTransformer for GWAS that includes five major modules （Transformer, Operator, Previewer, Coder and Simulator）. The toolkit not only works for transforming the genotyping files into ten input formats for use with classic genetics packages, but also carries out useful functions such as relational operations on IDs, previewing data files, recoding data formats and simulating marker files, among other functions. It bridges upstream raw genotyping data with downstream genetic programs, and can act as an in-hand toolkit for human geneticists, especially for non-programmers. SNPTransformer is freely available at http：//***.

关键词： genome-wide association studies tool genotyping files conversion

Casual associations between blood metabolites and colon cancer

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1995-2005页

作者： Ke-Yue Hu Yi-Quan Cheng Zhi-Long Shi Fu-Peng Ren Gang-Feng Xiao Department of Hematology and Oncology Ningbo No.2 HospitalNingbo 315000Zhejiang ProvinceChina

BACKGROUND Limited knowledge exists regarding the casual associations linking blood metabolites and the risk of developing colorectal cancer.AIM To investigate causal associations between blood metabolites and colon cancer.METHODS The study utilized a two-sample Mendelian randomization(MR)analysis to investigate the causal impact of 486 blood metabolites on colorectal cancer.The primary method of analysis used was the inverse variance weighted model.To further validate the results several sensitivity analyses were performed,including Cochran's Q test,MR-Egger intercept test,and MR robust adjusted profile score.These additional analyses were conducted to ensure the reliability and robustness of the findings.RESULTS After rigorous selection for genetic variation,486 blood metabolites were included in the MR analysis.We found Mannose[odds ratio(OR)=2.09(1.10-3.97),P=0.024],N-acetylglycine[OR=3.14(1.78-5.53),P=7.54×10^(-8)],X-11593-O-methylascorbate[OR=1.68(1.04-2.72),P=0.034],1-arachidonoylglycerophosphocholine[OR=4.23(2.51-7.12),P=6.35×10^(-8)]and 1-arachidonoylglycerophosphoethanolamine 4[OR=3.99(1.17-13.54),P=0.027]were positively causally associated with colorectal cancer,and we also found a negative causal relationship between Tyrosine[OR=0.08(0.01-0.63),P=0.014],Urate[OR=0.25(0.10-0.62),P=0.003],N-acetylglycine[0.73(0.54-0.98),P=0.033],X-12092[OR=0.89(0.81-0.99),P=0.028],Succinylcarnitine[OR=0.48(0.27-0.84),P=0.09]with colorectal cancer.A series of sensitivity analyses were performed to confirm the rigidity of the results.CONCLUSION This study showed a causal relationship between 10 blood metabolites and colorectal cancer,of which 5 blood metabolites were found to be causal for the development of colorectal cancer and were confirmed as risk factors.The other five blood metabolites are protective factors.

关键词： Metabolites Colon cancer Mendelian randomization genome-wide association studies Casual

Human-like adrenal features in Chinese tree shrews revealed by multi-omics analysis of adrenal cell populations and steroid synthesis

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Zoological Research 2024年第3期45卷 617-632页

作者： Jing-Hang Jiang Yi-Fu Wang Jie Zheng Yi-Ming Lei Zhong-Yuan Chen Yi Guo Ya-Jie Guo Bing-Qian Guo Yu-Fang Lv Hong-Hong Wang Juan-Juan Xie Yi-Xuan Liu Ting-Wei Jin Bi-Qi Li Xiao-Shu Zhu Yong-Hua Jiang Zeng-Nan Mo Center for Genomic and Personalized Medicine Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineGuangxi Key Laboratory for Genomic and Personalized MedicineGuangxi Medical UniversityNanningGuangxi 530021China Department of Urology First Affiliated Hospital of Guangxi Medical UniversityNanningGuangxi 530021China Reproductive Medicine Center Jingmen People’s HospitalJingChu University of Technology Affiliated Central HospitalJingmenHubei 448000China School of Computer Science and Engineering Yulin Normal UniversityYulinGuangxi 537000China Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry Guangxi Medical UniversityNanningGuangxi 530021China Department of Pathology Second Affiliated Hospital of Guangxi Medical UniversityNanningGuangxi 530007China Department of Obstetrics and Gynecology Second Affiliated Hospital of Guangxi Medical UniversityNanningGuangxi 530007China

The Chinese tree shrew(Tupaia belangeri chinensis)has emerged as a promising model for investigating adrenal steroid synthesis,but it is unclear whether the same cells produce steroid hormones and whether their production is regulated in the same way as in humans.Here,we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing,spatial transcriptome analysis,mass spectrometry,and immunohistochemistry.We compared the transcriptomes of various adrenal cell types across tree shrews,humans,macaques,and mice.Results showed that tree shrew adrenal glands expressed many of the same key enzymes for steroid synthesis as humans,including CYP11B2,CYP11B1,CYB5A,and CHGA.Biochemical analysis confirmed the production of aldosterone,cortisol,and dehydroepiandrosterone but not dehydroepiandrosterone sulfate in the tree shrew adrenal glands.Furthermore,genes in adrenal cell types in tree shrews were correlated with genetic risk factors for polycystic ovary syndrome,primary aldosteronism,hypertension,and related disorders in humans based on genome-wide association studies.Overall,this study suggests that the adrenal glands of Chinese tree shrews may consist of closely related cell populations with functional similarity to those of the human adrenal gland.Our comprehensive results(publicly available at http://***:16245/scAGMap/)should facilitate the advancement of this animal model for the investigation of adrenal gland disorders.

关键词： Tree shrew Adrenal gland Dehydroepiandrosterone genome-wide association studies Disease model

Empirical Saddlepoint Approximation and Its Application to genome-wide association studies

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Empirical Saddlepoint Approximation and Its Application to G...

A unified framework of detecting all kinds of effects in genome-wide association studies

第40届中国控制会议

作者： Yuzhuo Ma Wenjian Bi Ji-Feng Zhang Research Center for Mathematics and Interdisciplinary Sciences Shandong University Department of Medical Genetics Peking University Department of Biostatistics University of Michigan Academy of Mathematics and Systems Science Chinese Academy of Sciences School of Mathematical Sciences University of Chinese Academy of Sciences

This paper proposes a fast and accurate empirical saddlepoint approximation algorithm, EmpSPA, that is applicable for large-scale genome-wide association studies. Saddlepoint approximation（SPA） can utilize the entire cumulant-generating function（CGF）, which considerably improves the accuracy to approximate the null distribution of a test statistic. However, in some cases, it is technically challenging to calculate the expression of CGF, which limits the usage of SPA. We propose an empirical approach to estimating the CGF, which bypasses the technical challenge, and thus, is of high potential to be extended to complex traits analysis. Furthermore, the asymptotic equivalence property between SPA and EmpSPA is established. Finally,numeric simulations demonstrate that EmpSPA and SPA perform similarly, both of which are more accurate than regular normal distribution approximation.

关键词： genome-wide association studies saddlepoint approximation cumulant generating function complex traits analysis

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A unified framework of detecting all kinds of effects in gen...

Deciphering the chromatin spatial organization landscapes during BMMSC differentiation

第十九届中国作物学会学术年会

作者：章元明华中农业大学植物科技学院作物信息研究中心

The widely-used genome-wide association study(GWAS) methods in genetic dissection of complex traits in human, animal and plant genetics are almost based on single-marker genome scanning. These methods require Bonferroni correction for multiple tests, which often is too conservative to detect some important loci for complex traits, especially in relatively large experimental error. Meanwhile, the methodologies of detecting environmental(QE) and epistatic(QQ) interactions are limited. To overcome these issues, in the past a few years we have proposed six multi-locus GWAS methods. In these methods, first, various algorithms are used to scan each marker on the genome or all the markers on each chromosome or on the genome in order to obtain all the potentially associated markers. Then, all the selected markers are placed into one model, their effects are estimated by empirical Bayes, and all the non-zero effects are detected by likelihood ratio test for true QTN identification. A series of real and simulated datasets were analyzed by these multi-locus methods via an R software mrMLM v4.0. As a result, the power of QTN detection and the accuracy of QTN parameter estimation are significantly higher than those from the widely-used methods;false positive and negative rates in the detection of QTN are effectively controlled, although a more relaxed critical value(LOD=3.0 ≈ P-value = 0.0002) for significant QTN is adopted. Recently, we have constructed a unified framework for the detection of QE and QQ interactions in GWAS. Ten grain yield and quality traits in 1495 rice F1 s were re-analyzed. As a result, more than two hundred previously reported main-effect, QE and QQ genes are identified. All the above methods can promote the wide application of GWAS in human, animal and plant genetics.

关键词： genome-wide association studies mixed model rice QTN-by-environment interaction QTN-by-QTN interaction hybrid

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Journal of Genetics and Genomics 2023年第4期50卷 264-275页

作者： Zhaowei Teng Yun Zhu Da Lin Qinggang Hao Qiaoning Yue Xiaochao Yu Shuo Sun Lihong Jiang Sheng Lu Department of Orthopedics The First People's Hospital of Yunnan ProvinceAffiliated Hospital of Kunming University of Science and TechnologyKunmingYunnan 650032China Key Laboratory of Yunnan Provincial Innovative Application of Traditional Chinese Medicine The First People's Hospital of Yunnan ProvinceKunmingYunnan 650032China Clinical Medical Research Center The First People's Hospital of Yunnan ProvinceKunmingYunnan 650032China The Sixth Affiliated Hospital of Kunming Medical University YuxiYunnan 653100China State Key Laboratory of Agricultural Microbiology Huazhong Agricultural UniversityWuhanHubei 430070China Center for Life Sciences School of Life SciencesYunnan UniversityKunmingYunnan 650504China

The differentiation imbalance in bone marrow mesenchymal stem cells(BMMSCs)is critical for the development of bone density diseases as the population ages.BMMSCs are precursor cells for osteoblasts and adipocytes;however,the chromatin organization landscapes during BMMSC differentiation remain elusive.In this study,we systematically delineate the four-dimensional genome and dynamic epigenetic atlas of BMMSCs by RNA sequencing,assay for transposase-accessible chromatin sequencing,and highthroughput chromosome conformation capture.The structure analyses reveal 17.5%common and28.5%-30%specific loops among BMMSCs,osteoblasts,and adipocytes.The subsequent correlation of genome-wide association studies and expression quantitative trait locus(e QTL)data with multi-omics analysis reveal 274 genes and 3634 single nucleotide polymorphisms(SNPs)associated with bone degeneration and osteoporosis(OP).We hypothesize that SNP mutations affect transcription factor(TF)binding sites,thereby affecting changes in gene expression.Furthermore,26 motifs,260 TFs,and 291SNPs are identified to affect the e QTL.Among these genes,DAAM2,TIMP2,and TMEM241 are found to be essential for diseases such as bone degeneration and OP and may serve as potential drug targets.

关键词： Bone marrow mesenchymal stem cells Differentiation Hi-C ATAC-Seq Single nucleotide polymorphisms genome-wide association studies

Causal associations between inflammatory bowel disease and anxiety:A bidirectional Mendelian randomization study

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World Journal of Gastroenterology 2023年第44期29卷 5872-5881页

作者： Ying He Chun-Lan Chen Jian He Si-De Liu Department of Gastroenterology Nanfang HospitalSouthern Medical UniversityGuangzhou 510515Guangdong ProvinceChina Department of Infectious Diseases The Second Xiangya Hospital of Central South UniversityChangsha 410011Hunan ProvinceChina Department of Pulmonary and Critical Care Medicine Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou 510080Guangdong ProvinceChina

BACKGROUND Anxiety is common in patients with inflammatory bowel disease(IBD),including those with ulcerative colitis(UC)and Crohn’s disease(CD);however,the causal relationship between IBD and anxiety remains unknown.AIM To investigate the causal relationship between IBD and anxiety by using bidirectional Mendelian randomization analysis.METHODS Single nucleotide polymorphisms retrieved from genome-wide association studies(GWAS)of the European population were identified as genetic instrument variants.GWAS statistics for individuals with UC(6968 patients and 20464 controls;adults)and CD(5956 patients and 14927 controls;adults)were obtained from the International IBD Genetics Consortium.GWAS statistics for individuals with anxiety were obtained from the Psychiatric Genomics Consortium(2565 patients and 14745 controls;adults)and FinnGen project(20992 patients and 197800 controls;adults),respectively.Inverse-variance weighted was applied to assess the causal relationship,and the results were strengthened by heterogeneity,pleiotropy and leave-one-out analyses.RESULTS Genetic susceptibility to UC was associated with an increased risk of anxiety[odds ratio:1.071(95%confidence interval:1.009-1.135),P=0.023],while genetic susceptibility to CD was not associated with anxiety.Genetic susceptibility to anxiety was not associated with UC or CD.No heterogeneity or pleiotropy was observed,and the leave-one-out analysis excluded the potential influence of a particular variant.CONCLUSION This study revealed that genetic susceptibility to UC was significantly associated with anxiety and highlighted the importance of early screening for anxiety in patients with UC.

关键词： Inflammatory bowel disease Anxiety Causal effect Mendelian randomization genome-wide association studies

Pathogenesis of premature coronary artery disease:Focus on risk factors and genetic variants

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Genes & Diseases 2022年第2期9卷 370-380页

作者： Haiming Wang Zifan Liu Junjie Shao Min Jiang Xuechun Lu Lejian Lin Lin Wang Qiang Xu Haomin Zhang Xin Li Jingjing Zhou Yundai Chen Ran Zhang Department of Cardiovascular Medicine Chinese PLA General Hospital&Chinese PLA Medical SchoolBeijing 100853PR China The First Clinical Medical College of Inner Mongolia Medical University Hohhot 010059PR China Department of Hematology The Second Medical Center of Chinese PLA General Hospital&Chinese PLA Medical SchoolBeijing 100853PR China Department of Health Services The First Medical Center of Chinese PLA General Hospital&Chinese PLA Medical SchoolBeijing 100853PR China

The development of premature coronary artery disease(PCAD)is dependent on both genetic predisposition and traditional risk factors.Strategies for unraveling the genetic basis of PCAD have evolved with the advent of modern technologies.genome-wide association studies(GWASs)have identified a considerable number of common genetic variants that are associated with PCAD.Most of these genetic variants are attributable to lipid and blood pressure-related single-nucleotide polymorphisms(SNPs).The genetic variants that predispose individuals to developing PCAD may depend on race and ethnicity.Some characteristic genetic variants have been identified in Chinese populations.Although translating this genetic knowledge into clinical applications is still challenging,these genetic variants can be used for CAD phenotype identification,genetic prediction and therapy.In this article we will provide a comprehensive review of genetic variants detected by GWASs that are predicted to contribute to the development of PCAD.We will highlight recent findings regarding CAD-related genetic variants in Chinese populations and discuss the potential clinical utility of genetic variants for preventing and managing PCAD.

关键词： Genetic clinical applications Genetic variants genome-wide association studies Premature coronary artery disease Single-nucleotide polymorphisms