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Investigating the Contribution of coding variants in Alcohol Use Disorder Using Whole-Exome Sequencing Across Ancestries

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Biological Psychiatry 2025年

作者： Wang, Lu Kranzler, Henry R. Gelernter, Joel Zhou, Hang Department of Psychiatry Yale University School of Medicine New Haven Connecticut United States Veterans Affairs Connecticut Healthcare System West Haven CT United States Department of Psychiatry University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania United States Crescenz Veterans Affairs Medical Center Philadelphia Pennsylvania United States Department of Genetics Yale School of Medicine New Haven Connecticut United States Department of Neuroscience Yale School of Medicine New Haven Connecticut United States Department of Biomedical Informatics and Data Science Yale School of Medicine New Haven Connecticut United States Center for Brain and Mind Health Yale School of Medicine New Haven Connecticut United States

Background: Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. There has been substantial progress in identifying genetic variants that underlie AUD. However, whole-exome sequencing studies of AUD have been hampered by the lack of available samples. Methods: We analyzed whole-exome sequencing data of 4530 samples from the Yale-Penn cohort and 469,835 samples from the UK Biobank, which represent an unprecedented resource for exploring the contribution of coding variants in AUD. After quality control, 1750 African-ancestry (1142 cases) and 2039 European-ancestry (1420 cases) samples from the Yale-Penn and 6142 African-ancestry (130 cases), 415,617 European-ancestry (12,861‬ cases), and 4607 South Asian (130 cases) samples from the UK Biobank cohorts were included in the analyses. Results: We confirmed the well-known functional variant rs1229984 in ADH1B (p = 4.88 × 10⁻³¹) and several other variants in ADH1C. Gene-based collapsing tests that considered the high allelic heterogeneity revealed the previously unreported genes CNST (p = 1.19 × 10⁻⁶), attributable to rare variants with allele frequency < 0.001, and IFIT5 (p = 3.74 × 10⁻⁶), driven by the burden of both common and rare loss-of-function and missense variants. Conclusions: This study extends our understanding of the genetic architecture of AUD by providing insights into the contribution of rare coding variants, separately and convergently with common variants in AUD. © 2025 Society of Biological Psychiatry

关键词： Alcohol use disorder coding variants Multiancestry Rare variants Substance use disorder Whole-exome sequencing

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Chip-based direct genotyping of coding variants in genome wide association studies: Utility, issues and prospects

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GENE 2014年第1期540卷 104-109页

作者： Nievergelt, Caroline M. Wineinger, Nathan E. Libiger, Ondrej Phillip Pham Zhang, Guangfa Baker, Dewleen G. Schork, Nicholas J. Univ Calif San Diego Dept Psychiat La Jolla CA 92093 USA VA San Diego VA Ctr Excellence Stress & Mental Hlth San Diego CA USA Scripps Hlth Scripps Genom Med San Diego CA USA Scripps Res Inst Scripps Translat Sci Inst San Diego CA USA

There is considerable debate about the most efficient way to interrogate rare coding variants in association studies. The options include direct genotyping of specific known coding variants in genes or, alternatively, sequencing across the entire exome to capture known as well as novel variants. Each strategy has advantages and disadvantages, but the availability of cost-efficient exome arrays has made the former appealing. Here we consider the utility of a direct genotyping chip, the Illumina HumanExome array (HE), by evaluating its content based on: 1. functionality: and 2. amenability to imputation. We explored these issues by genotyping a large, ethnically diverse cohort on the HumanOmniExpressExome array (HOEE) which combines the HE with content from the GWAS array (HOE). We find that the use of the HE is likely to be a cost-effective way of expanding GWAS, but does have some drawbacks that deserve consideration when planning studies. (C) 2014 Elsevier B.V. All rights reserved.

关键词： Illumina HumanExome array Expanding GWAS Genotyping rare SNPs coding variants

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Mapping leprosy-associated coding variants of interleukin genes by targeted sequencing

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CLINICAL GENETICS 2021年第6期99卷 802-811页

作者： Zhang, Deng-Feng Li, Hui-Long Zheng, Quanzhen Bi, Rui Xu, Min Wang, Dong Zhu, Guo-Ping Li, Yu-Ye Yao, Yong-Gang Chinese Acad Sci KIZ CUHK Joint Lab Bioresources & Mol Res Common Key Lab Anim Models & Human Dis Mechanisms Chinese Acad Sci & Yunnan ProvKunming Inst Zool Kunming Yunnan Peoples R China Chinese Acad Sci Ctr Excellence Anim Evolut & Genet Kunming Yunnan Peoples R China Univ Chinese Acad Sci Kunming Coll Life Sci Kunming Yunnan Peoples R China Anhui Normal Univ Coll Life Sci Wuhu Peoples R China Chinese Acad Sci Ctr Excellence Brain Sci & Intelligence Technol Shanghai Peoples R China Kunming Med Univ Affiliated Hosp 1 Dept Dermatol Kunming Yunnan Peoples R China

Previous genotyping-based assays have identified non-coding variants of several interleukins (ILs) being associated with genetic susceptibility to leprosy. However, understanding of the involvement of coding variants within all IL family genes in leprosy was still limited. To obtain the full mutation spectrum of all ILs in leprosy, we performed a targeted deep sequencing of coding regions of 58 ILs genes in 798 leprosy patients (age 56.2 +/- 14.4;female 31.5%) and 990 healthy controls (age 38.1 +/- 14.0;female 44.3%) from Yunnan, Southwest China. mRNA expression alterations of ILs in leprosy skin lesions or in response to M. leprae treatment were estimated by using publicly available expression datasets. Two coding variants in IL27 (rs17855750, p.S59A, p = 4.02 x 10(-8), odds ratio [OR] = 1.748) and IL1RN (rs45507693, p.A106T, p = 1.45 x 10(-5), OR = 3.629) were significantly associated with leprosy risk. mRNA levels of IL27 and IL1RN were upregulated in whole blood cells after M. leprae stimulation. These data showed that IL27 and IL1RN are leprosy risk genes. Further functional study is required for characterizing the exact role of ILs in leprosy.

关键词： coding variants genetic susceptibility interleukin leprosy next generation sequencing

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Myocilin and optineurin coding variants in Hispanics of Mexican descent with POAG

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JOURNAL OF HUMAN GENETICS 2010年第10期55卷 697-700页

作者： McDonald, Kristin K. Abramson, Karen Beltran, Marco A. Ramirez, Maria G. Alvarez, Miguel Ventura, Alice Santiago-Turla, Cecilia Schmidt, Silke Hauser, Michael A. Allingham, R. Rand Duke Univ Med Ctr Ctr Human Genet Durham NC 27710 USA Clin Oftalmol Hermosillo Sonora Mexico Oftalmologos Asociados Nogales Sonora Mexico Duke Univ Med Ctr Ctr Eye Dept Ophthalmol Durham NC 27710 USA

coding variants in both myocilin (MYOC) and optineurin (OPTN) are reported risk factors for primary open-angle glaucoma (POAG) in many populations. This study investigated the contribution of MYOC and OPTN coding variants in Hispanics of Mexican descent with and without POAG. We conducted a case-control study of unrelated POAG cases and nonglaucomatous controls in a population of Hispanics of Mexican descent. Ascertainment criteria for POAG included the presence of glaucomatous optic neuropathy with associated visual field loss and the absence of secondary causes of glaucoma. Controls had normal optic nerves, visual fields and intraocular pressure. All coding exons of MYOC and OPTN were sequenced. The data set consisted of 88 POAG cases and 93 controls. A novel nonsynonymous coding variant (R7H) in the first exon of MYOC was identified. Other identified variants in MYOC and OPTN have been previously described and do not seem to contribute to POAG risk. This is the first comprehensive study of MYOC and OPTN in Hispanics of Mexican descent with POAG. Neither MYOC nor OPTN sequence variants seem to have a major role in the etiology of POAG in this population. Journal of Human Genetics (2010) 55, 697-700;doi:10.1038/jhg.2010.91;published online 29 July 2010

关键词： coding variants myocilin optineurin primary open-angle glaucoma

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A quantitative pipeline to assess secretion of human leptin coding variants reveals mechanisms underlying leptin deficiencies

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JOURNAL OF BIOLOGICAL CHEMISTRY 2024年第8期300卷 107562-107562页

作者： Baird, Harry J. M. Shun-Shion, Amber S. de Oliveira, Edson Mendes Stalder, Daniele Liang, Lu Eden, Jessica Chambers, Joseph E. Farooqi, I. Sadaf Gershlick, David C. Fazakerley, Daniel J. Univ Cambridge Inst Metab Sci Metab Res Lab Cambridge England Univ Cambridge Cambridge Inst Med Res Cambridge England

The hormone leptin, primarily secreted by adipocytes, plays a crucial role in regulating whole-body energy homeostasis. Homozygous loss-of-function mutations in the leptin gene (LEP) cause hyperphagia and severe obesity, primarily through alterations in leptin's affinity for its receptor or changes in serum leptin concentrations. Although serum concentrations are influenced by various factors (e.g., gene expression, protein synthesis, stability in the serum), proper delivery of leptin from its site of synthesis in the endoplasmic reticulum via the secretory pathway to the extracellular serum is a critical step. However, the regulatory mechanisms and specific machinery involved in this trafficking route, particularly in the context of human LEP mutations, remain largely unexplored. We have employed the Retention Using Selective Hooks system to elucidate the secretory pathway of leptin. We have refined this system into a medium-throughput assay for examining the pathophysiology of a range of obesity-associated LEP variants. Our results reveal that leptin follows the default secretory pathway, with no additional regulatory steps identified prior to secretion. Through screening of leptin variants, we identified three mutations that lead to proteasomal degradation of leptin and one variant that significantly decreased leptin secretion, likely through aberrant disulfide bond formation. These observations have identified novel pathogenic effects of leptin variants, which can be informative for therapeutics and diagnostics. Finally, our novel quantitative screening platform can be adapted for other secreted proteins.

关键词： leptin secretion coding variants adipokine

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Advances in identifying coding variants of common complex diseases

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Journal of Bio-X Research 2019年第4期2卷 153-158页

作者： Cai Minglong Ran Delin Zhang Xuejun Department of Dermatology the First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui ProvinceChina Institute of Dermatology Anhui Medical UniversityHefeiAnhui ProvinceChina Key Laboratory of Dermatology(Anhui Medical University) Ministry of EducationHefeiAnhui ProvinceChina State Key Laboratory Incubation Base of Dermatology Anhui Medical UniversityHefeiAnhui ProvinceChina Anhui Province Key Laboratory of Major Autoimmune Diseases HefeiAnhui ProvinceChina

Many common diseases are characterized by polygenic architectures in which a single variant has only a small effect on ***-wide association studies and next generation sequencing have identified thousands of genetic variants of disease ***,non-coding variants identified by genome-wide association studies have been systematically ***,we review disease-causing coding variants and their relevance to clinical medicine.

关键词： common diseases GWAS next generation sequencing coding variants non-coding variants

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Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants

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AMERICAN JOURNAL OF HUMAN GENETICS 2025年第4期112卷 863-875页

作者： Fries, Lauren E. Dharma, Sree Chakravarti, Aravinda Chatterjee, Sumantra NYU Ctr Human Genet & Genom Grossman Sch Med New York NY 10016 USA NYU Grossman Sch Med Dept Neurosci & Physiol New York NY 10016 USA

Hirschsprung disease (HSCR) exhibits extensive genetic heterogeneity, with 72% of cases involving pathogenic variants in 10 genes forming a gene regulatory network (GRN) essential for enteric nervous system (ENS) development. The receptor tyrosine kinase gene RET is the most significant contributor, implicated in 12%-50% of individuals depending on the phenotype. RET plays a critical role in ENS precursor proliferation and migration, and defects in these processes lead to HSCR. However, the functional impact of RET pathogenic variants and their mechanisms of disease remain poorly understood. To address this, we investigated proliferative and migratory phenotypes in a RET-dependent neural crest-derived cell line harboring one of five missense (c.166C>A [***56Met];c.532G>C [***178Gln];c.2372A>T [***791Phe];c.2765C>A [***922Tyr];or c.2994T>A [***998Leu]) or three nonsense (c.612C>A, c.2308C>T, or c.2943C>G) heterozygous pathogenic RET variants. Using cDNA- and CRISPR-based prime reverse insertion mechanism engineering (PRIME) editing coupled with quantitative proliferation and migration assays, we observed significant losses in proliferation and migration in three missense (c.612C>A [***204(& lowast;)];c.2308C>T [***770(& lowast;)];and c.2943C>G [***981(& lowast;)]) and all nonsense variants. Notably, the c.2372A>T (***791Phe) missense variant, whose pathogenicity has been debated, appears benign. Importantly, the severity of migration loss did not consistently correlate with proliferation defects, and the phenotypic severity of nonsense variants was independent of their position within the RET protein. This study highlights the necessity of targeted functional assays to accurately assess the pathogenicity of HSCR-associated variants rather than relying solely on bioinformatics predictions, which could be refined by incorporating functional data.

关键词： Hirschsprung disease functional validation PRIME editing RET coding variants genome engineering migration assay proliferation assay

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Whole exome sequencing based coding variation in nasopharyngeal cancer from tribal population of North-East India

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GENE REPORTS 2025年 38卷

作者： Ghosh, Sudip Kumar Das Kundu, Raima Ghosh, Sankar Kumar Assam Univ Silchar 788011 Assam India RKMVERI Howrah 711202 West Bengal India InBOL Healthcare Educ Ctr 28-2G N B Lane Kalighat 700026 West Bengal India

Genome-wide association studies (GWAS) have emerged due to the advent of high-throughput genotyping tools in the study of genetic architecture. Next-generation sequencing techniques, particularly whole exome sequencing (WES) in single nucleotide polymorphism (SNP) analysis, have been used to identify unusual coding variations. Across various demographic groups worldwide, coding differences have varied impacts on the evolution of NPC. However, certain loci related to NPC susceptibility are shared by multiple population types, with the North Eastern (NE) region exhibiting ethnicity-specific cancer variations. In this study, we focused on the major North Eastern tribal populations (Mizoram, Manipur, and Nagaland) to identify NPC-focused germline coding variations through WES. To better understand the genetic association of coding variants with NPC, WES was performed on 15 samples from affected patients and healthy individuals from three different ethnic groups (N = 9 cases and N = 6 controls). variants were called using the Ion ProtonTM platform, and case-control variants were screened for their association studies. All variants were filtered using Haploview, and PLINK software was used to assess the statistical significance of the passed case-control variants. Furthermore, the filtered variants, along with significant variants, were analyzed using different bioinformatics tools and compared with other clinical databases. A total of 60,387 (61.50 %) variations were discovered, of which 578 (p-value <= 0.05) were determined to be significant coding variants. These variants were then processed and filtered using several in silico techniques. The coding regions (exonic) of 10 genes, including CR1, GBP3, QPCT, ADGRV1, ADGB, ALG9, DLAT, CCT6B, GP6, and LRRN4, revealed ten SNPs, all of which are thought to be strongly linked with the NPCs of the three main NER tribes. It is anticipated that protein stability varies as a result of mutation, based on different in silico softwa

关键词： Genome wide association study (GWAS) Nonsynonymous SNPs (nsSNP) North-East (NE) Nasopharyngeal carcinoma (NPC) Whole exome sequencing (WES) coding variants

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Association analysis of potentially functional variants within 8p12 with schizophrenia in the Han Chinese population

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WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY 2021年第1期22卷 27-33页

作者： Chen, Ruirui Chen, Jianhua Gao, Chengwen Wu, Chuanhong Pan, Dun Zhang, Jinmai Zhou, Juan Wang, Ke Zhang, Qian Yang, Qiangzhen Jian, Xuemin Zhao, Yalin Wen, Yanqin Wang, Zhuo Shi, Yongyong Li, Zhiqiang Qingdao Univ Sch Basic Med Qingdao Peoples R China Qingdao Univ Affiliated Hosp 16 Jiangsu Rd Qingdao 266003 Peoples R China Qingdao Univ Biomed Sci Inst Qingdao Branch SJTU BioX Inst 16 Jiangsu Rd Qingdao 266003 Peoples R China Shanghai Jiao Tong Univ Collaborat Innovat Ctr Brain Sci BioX Inst Key Lab Genet Dev & Neuropsychiat DisordersMinis Shanghai Peoples R China Shanghai Jiao Tong Univ Inst Social Cognit & Behav Sci Shanghai Peoples R China Shanghai Jiao Tong Univ Inst Neuropsychiat Sci & Syst Biol Med Shanghai Peoples R China

Objectives: Chromosome 8p12 was first identified as a schizophrenia (SCZ) risk locus in Chinese populations and replicated in European populations. However, the underlying functional variants still need to be further explored. In this study, we sought to identify plausible causal variants within this locus. Methods: A total of 386 potentially functional variants from 29 genes within the 8p12 locus were analysed in 2403 SCZ cases and 2594 control subjects in the Han Chinese population using Affymetrix customised genotyping assays. SHEsisplus was used for association analysis. A multiple testing corrected p value (false discovery rate (FDR)) < .05 was considered significant, and an unadjusted p value < .05 was considered nominal evidence of an association. Results: We did not find significant associations between the tested variants and SCZ. However, nominal associations were found for rs201292574 (unadjusted p = .033, FDR p = .571;95% confidence interval (CI): 0.265-0.945;TACC1, NP_006274.2:***211Thr) and rs45563241 (unadjusted p = .039, FDR p = .571;95% CI: 1.023-1.866;a synonymous mutation in ADRB3). Conclusions: Our results provide limited evidence for the associations between variants from protein coding regions in 8p12 and SCZ in the Chinese population. Analyses of both coding and regulatory variants in larger sample sizes are required to further clarify the causal variants for SCZ with this risk locus.

关键词： Schizophrenia 8p12 locus Chinese population fine-mapping coding variants

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Genetic variants in FBLIM1 gene do not contribute to SAPHO syndrome and chronic recurrent multifocal osteomyelitis in typical patient groups

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BMC MEDICAL GENETICS 2020年第1期21卷 102-102页

作者： Assmann, Gunter Koehm, Michaela Schuster, Volker Behrens, Frank Moessner, Rotraut Magnolo, Nina Oji, Vinzenz Burkhardt, Harald Hueffmeier, Ulrike Univ Saarland Sch Med Jose Carreras Ctr Immuno & Gene Therapy Dept Internal Med 1 Homburg Germany Goethe Univ Fraunhofer Inst Div Rheumatol Frankfurt Germany Goethe Univ Fraunhofer Inst IME Branch Translat Med & Pharmacol Frankfurt Germany Univ Leipzig Hosp Children & Adolescents Leipzig Germany Georg August Univ Gottingen Dept Dermatol Gottingen Germany Univ Munster Dept Dermatol Munster Germany Friedrich Alexander Univ Erlangen Nurnberg Univ Hosp Erlangen Inst Human Genet Schwabachanlage 10 D-91054 Erlangen Germany

Background Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) present two diseases of a dermatologic and rheumatologic spectrum that are variable in manifestation und therapeutic response. Genetic risk factors have long been assumed in both diseases, but no single reliable factor has been identified yet. Therefore, we aimed to clinically characterize a patient group with syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) (n = 47) and chronic recurrent multifocal osteomyelitis (CRMO)/ chronic non-bacterial osteomyelitis (CNO) (n = 9) and analyze a CRMO candidate gene. Methods Clinical data of all patients were collected and assessed for different combinations of clinical symptoms. SAPHO patients were grouped into categories according to the acronym;disease-contribution by pathogens was evaluated. We sequenced coding exons of FBLIM1. Results Palmoplantar pustular psoriasis (PPP) was the most common skin manifestation in CRMO/CNO and SAPHO patients;most SAPHO patients had sterno-costo-clavicular hyperostosis. The most common clinical category of the acronym was S_PHO (n = 26). Lack of pathogen detection from bone biopsies was more common than microbial isolation. We did not identify autosomal-recessive FBLIM1 variants. Conclusions S_PHO is the most common combination of symptoms of its acronym. Genetic analyses of FBLIM1 did not provide evidence that this gene is relevant in our patient group. Our study indicates the need to elucidate SAPHO's and CRMO/CNO's pathogenesis.

关键词： Chronic recurrent multifocal osteomyelitis (CRMO) Chronic non-bacterial osteomyelitis (CNO) Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO (syndrome)) coding variants Association

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