Bridging the gap between type 2 diabetes GWAS and therapeutic targets

缩小 2 型糖尿病 GWAS 与治疗目标之间的差距

• 批准号: 10649602
• 负责人: Melina C Claussnitzer
• 金额: $ 186.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649602
• 关键词: Acceleration; Address; Adipocytes; Adipose tissue; Affect; African; Alleles; Animal Model; Biological; Biological Assay; Catalogs; Cell model; Cells; Chromatin; Collaborations; Collection; Communities; Complement; Computer Analysis; Computing Methodologies; DNA; DNA Sequence; Data; Data Set; Disease; Distant; Drug Targeting; East Asian; Electrophysiology (science); Environment; Ethnic Origin; European; Evaluation; Frequencies; Functional disorder; Generations; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Gluconeogenesis; Hepatic Tissue; Hepatocyte; Heritability; Hispanic; Human; Human Genetics; Impairment; Individual; Inherited; Insulin; Insulin deficiency; International; Investigation; Islet Cell; Latino; Link; Lipids; Liver; Maps; Meta-Analysis; Methods; Mitochondria; Molecular; Morbidity - disease rate; Muscle; Muscle Cells; Names; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Nucleotides; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Population; Population Heterogeneity; Regulation; Regulatory Element; Research Personnel; Resistance; Role; Series; Signal Pathway; Signal Transduction; South Asian; Structure of beta Cell of islet; System; Testing; Tissues; Transcript; Translating; Untranslated RNA; Validation; Variant; Vision; Visualization; analytical method; candidate marker; causal variant; cell type; clinical phenotype; computerized tools; diabetes mellitus genetics; diabetes pathogenesis; diabetes risk; disease heterogeneity; disorder risk; epigenomics; experimental study; functional genomics; gene regulatory network; genetic architecture; genetic association; genetic variant; genome annotation; genome editing; genome wide association study; genome-wide; genome-wide analysis; genomic data; glucose uptake; improved; in vivo; insight; insulin secretion; islet; lipid metabolism; mortality; multidisciplinary; new therapeutic target; novel; novel therapeutic intervention; pancreatic juice; protein function; risk variant; skeletal tissue; therapeutic target; trait; transcriptomics

Type 2 diabetes (T2D) is a heterogeneous disorder characterized by resistance of hepatic, skeletal muscle and adipose tissues to insulin and a relative deficiency of insulin secretion by pancreatic β cells. T2D has a substantial genetic component, and over the past decade human genetic studies have identified over 400 association signals across diverse populations. However, in most cases the specific variants and genes responsible for these association signals are not known. T2D signals include loci for which functions of the protein products encoded by nearby genes are poorly characterized, the closest known gene is distant, or more than one gene appears to be a plausible biological candidate. Identifying the causal variants, the regulatory gene networks affected by the change in DNA sequence, and the mechanisms by which such variation leads to disease are critical steps toward understanding the genetic architecture of T2D, validating potential drug targets, and developing novel therapeutic strategies. Here, we propose large-scale multi-disciplinary functional genomics projects in islet, liver, adipose and muscle cells to determine the contributions and mechanisms underlying T2D risk-associated variants and their downstream effector transcripts. Throughout the project, we leverage our prior and ongoing generation of genomic data sets and genome-wide and targeted screens for function of variants and genes. To complement these efforts, we will first collect genome-wide array and sequencing-based association study results, identify conditionally distinct association signals and construct credible sets of variants. We propose to link variants to effector transcripts through analyses of genome-wide transcriptomic and epigenomic data, perturbation assays that alter thousands of variant-containing regulatory elements and effector transcripts, perturbations of tens of specific variants, and integrative computational analyses. Next, we propose systematic evaluation of hundreds of potential effector transcripts through use of genome-wide and targeted screens of insulin secretion, lipid accumulation, mitochondrial function, glucose uptake, and differentiation state, with assay selection depending on cell type. Based on these results, we propose focused studies on tens to hundreds of potential effector transcripts to evaluate electrophysiology, gluconeogenesis, lipid metabolism and signaling pathways, and we propose thorough investigation the context-specific mechanism of action of individual genes. Finally, we propose to analyze, integrate, and visualize all data by placing effector transcripts into cell-type and environmental context-specific networks, selecting network nodes as candidate biomarkers and modulation points for drugs, and building a framework to understand the tissue-specific contribution of variants and transcripts to individual disease heterogeneity. Successful completion of these aims will translate T2D association signals into biological insights and therapeutic targets.

2型糖尿病（T2D）是一种以肝脏、骨骼肌和肝脏抵抗为特征的异质性疾病

项目成果

Genetics of Type 2 Diabetes: Opportunities for Precision Medicine: JACC Focus Seminar.

• DOI: 10.1016/j.jacc.2021.03.346
• 发表时间: 2021-08-03
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Kim DS;Gloyn AL;Knowles JW
• 通讯作者: Knowles JW

100 YEARS OF INSULIN: A brief history of diabetes genetics: insights for pancreatic beta-cell development and function.

• DOI: 10.1530/joe-21-0067
• 发表时间: 2021-07-22
• 期刊: JOURNAL OF ENDOCRINOLOGY
• 影响因子: 4
• 作者: Ikle, Jennifer M.;Gloyn, Anna L.
• 通讯作者: Gloyn, Anna L.

Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity.

2 型糖尿病的多祖先多基因机制阐明了疾病过程和临床异质性。

• DOI: 10.1101/2023.09.28.23296294
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Smith,Kirk;Deutsch,AaronJ;McGrail,Carolyn;Kim,Hyunkyung;Hsu,Sarah;Mandla,Ravi;Schroeder,PhilipH;Westerman,KennethE;Szczerbinski,Lukasz;Majarian,TimothyD;Kaur,Varinderpal;Williamson,Alice;Claussnitzer,Melina;Florez,JoseC;Ma
• 通讯作者: Ma

The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion.

• DOI: 10.1038/s43856-023-00369-8
• 发表时间: 2023-10-05
• 期刊: COMMUNICATIONS MEDICINE
• 作者: Murphy, Rinki;Colclough, Kevin;Pollin, Toni I;Ikle, Jennifer M;Svalastoga, Pernille;Maloney, Kristin A;Saint-Martin, Cecile;Molnes, Janne;Misra, Shivani;Aukrust, Ingvild;de Franco, Elisa;Flanagan, Sarah E;Njolstad, Pal R;Billings, Liana K;Owen, Katharine R;Gloyn, Anna L
• 通讯作者: Gloyn, Anna L

A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk.

• DOI: 10.1038/s41588-022-01261-2
• 发表时间: 2023-01
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Rottner, Antje K.;Ye, Yingying;Navarro-Guerrero, Elena;Rajesh, Varsha;Pollner, Alina;Bevacqua, Romina J.;Yang, Jing;Spigelman, Aliya F.;Baronio, Roberta;Bautista, Austin;Thomsen, Soren K.;Lyon, James;Nawaz, Sameena;Smith, Nancy;Wesolowska-Andersen, Agata;Fox, Jocelyn E. Manning;Sun, Han;Kim, Seung K.;Ebner, Daniel;MacDonald, Patrick E.;Gloyn, Anna L.
• 通讯作者: Gloyn, Anna L.