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Genetics in Diabetes Type 2 Diabetes and Related Traits 1st Edition by Gloyn, Mccarthy, Porta, Matschinsky 3318026999 978-3318026993

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ISBN 10: 3318026999

ISBN 13: 978-3318026993

Author: A. L. Gloyn, M. I. Mccarthy, M. Porta, F. M. Matschinsky

Over the past decade, there has been unprecedented progress in our understanding of the genetic basis of type 2 diabetes driven largely by technological advances which have facilitated genome-wide studies. Bringing together comprehensive synopses written by leaders in the field, this book discusses the recent progress in defining the genetic basis for type 2 diabetes and related traits. The opening section focuses on the impact of genome-wide association studies on our understanding of the genetic landscape of type 2 diabetes, whilst later chapters explore how variants affecting relevant metabolic traits influence diabetes susceptibility. The impact of next-generation sequencing on gene discovery efforts in both type 2 diabetes and mendelian forms of diabetes and insulin resistance is covered in detail. Particular attention is also given to efforts to increase our understanding of sequence annotation in diabetes-relevant tissues and how this can be harnessed to leverage molecular mechanisms for genetic association signals. Finally, efforts to translate this improved knowledge into both molecular mechanisms and clinical care are discussed. Providing a comprehensive overview of the current knowledge of the genetic basis for type 2 diabetes and related traits, this book is essential reading for researchers with an interest in the etiology of diabetes and human genetics.

Table of contents:

  1. Genome-Wide Association Study Discovery for T2D
  2. Turning Genome-Wide Association Study Discoveries into Functional Insights
  3. Cross-Trait Analyses Illuminate Biological Relationships between Related Phenotypes
  4. T2D-Associated Variants Act Predominantly via Insulin Secretion Rather Than Peripheral Insulin Sensitivity
  5. Physiological and Pathological Variation in Glycaemia Is Genetically Distinct
  6. The Role of Dyslipidaemia in T2D Risk
  7. A Genetic Contribution to the Relationship between Early Growth and Subsequent T2D Risk
  8. Defining Pathogenetic Pathways through Enrichment Analyses in Genome-Wide Association Study Loci
  9. Genome-Wide Association Study Provides Insights into the Origins of the Genetic Contribution to T2D Risk
  10. Defining Mechanisms at the Level of Individual Loci
  11. Conclusions
  12. Acknowledgements
  13. References
  14. Fine Mapping Type 2 Diabetes Susceptibility Loci
  15. Abstract
  16. Assaying Genetic Variation for the Fine-Mapping of Complex Trait Loci
  17. Custom-Designed Genotyping Arrays
  18. Imputation
  19. Methodology for the Fine-Mapping of Complex Trait Loci
  20. Defining ‘Credible Sets’ of Causal Variants
  21. Assessing the Evidence for Allelic Heterogeneity
  22. Combining GWAS from Multiple Ancestry Groups
  23. Incorporating Functional Annotation and/or Evidence from Biological Resources
  24. Progress in Fine-Mapping T2D Susceptibility Loci
  25. Widespread Allelic Heterogeneity at T2D Susceptibility Loci
  26. Lack of Evidence for Low-Frequency Causal Alleles
  27. TransEthnic Meta-Analysis and Fine-Mapping
  28. Integration of Functional Annotation and Biological Resources
  29. Perspectives
  30. References
  31. Whole Genome and Exome Sequencing of Type 2 Diabetes
  32. Abstract
  33. Sample Selection Strategies and Study Design
  34. High-Throughput Sequencing Technologies
  35. Testing Specific Hypotheses of Variant Contribution to T2D
  36. Statistical Approaches for Analysis of Sequence Variants
  37. Correcting for Confounders in Sequence Analysis
  38. Follow-Up and Replication Strategies
  39. Conclusions
  40. References
  41. Gene Discovery Efforts for Glycaemic and Metabolic Traits
  42. Genome-Wide Association Studies of Glycaemic Traits: A MAGICal Journey
  43. Abstract
  44. Background
  45. Why Glycaemic Traits?
  46. Loci Influencing Glycaemic Traits
  47. Fasting Glucose, Fasting Insulin and 2-Hour Glucose Traits
  48. HbA1c
  49. Proinsulin
  50. What Have These Efforts Taught Us?
  51. From Intermediate Traits to Disease
  52. Intermediate Traits to Dissect Disease Pathways
  53. Sociology of Science
  54. Future Directions
  55. References
  56. Genome-Wide Association Studies of Obesity and Related Traits
  57. Abstract
  58. Genetic Architecture of Obesity Traits
  59. Biology and Mechanisms Underlying Obesity Traits
  60. Future Directions
  61. References
  62. Gene Discovery Efforts for Monogenic Disorders of β-Cell Dysfunction and Insulin Resistance
  63. Next-Generation Sequencing for the Diagnosis of Monogenic Diabetes and Discovery of Novel Aetiologies
  64. Abstract
  65. Introduction to Monogenic Diabetes
  66. Stratified Treatment for Monogenic Diabetes
  67. Known Causes of Monogenic Diabetes
  68. Next-Generation Sequencing
  69. Targeted Next-Generation Sequencing for Monogenic Diabetes
  70. Methods
  71. A Targeted Capture Assay for Monogenic Diabetes
  72. Exome Sequencing for Novel Disease Gene Discovery in Monogenic Diabetes
  73. Methods
  74. Analysis Strategies
  75. Examples of Exome Sequencing in Monogenic Diabetes
  76. Concluding Remarks
  77. Acknowledgements
  78. References
  79. Whole-Exome Sequencing of Patients with Severe Disorders of Insulin Action
  80. Abstract
  81. Background
  82. Syndromes of Severe Insulin Resistance
  83. Challenges in Genetic Study of Disordered Insulin Action
  84. Genetic Defects Implicated in Severe Insulin Resistance without Massively Parallel Sequencing
  85. Whole Exome Sequencing
  86. Insights Gained from Whole-Exome Sequencing of Severe Disorders of Insulin Action
  87. Early Diagnosis of Disease
  88. Diagnosis of Atypical or Misclassified Disease
  89. New Diagnosis
  90. Conclusions
  91. References
  92. ‘Omics’ of Type 2 Diabetes and Related Traits
  93. Epigenetic Modifications and Type 2 Diabetes in Humans
  94. Abstract
  95. Epigenetic Modifications in Patients with Type 2 Diabetes
  96. Non-Genetic Risk Factors and Epigenetic Modifications in Target Tissues for Type 2 Diabetes
  97. Impact of Genetic Factors on Epigenetic Modifications
  98. Conclusion
  99. References
  100. Insights into β-Cell Biology and Type 2 Diabetes Pathogenesis from Studies of the Islet Transcriptome
  101. Abstract
  102. Human Pancreatic Islets Play a Key Role in Diabetes Mellitus
  103. Transcriptome Analysis Provides Powerful Tools for Understanding Biology and Disease
  104. Islet Transcriptome Data and Mechanistic Insights at T2D Association Loci
  105. Islet Transcriptome Analysis and Novel Biomarkers for Islet Dysfunction
  106. The Role of Long Non-Coding RNAs in the Pancreatic Islets
  107. The Human Islet Transcriptome and β-Cell Programming Efforts
  108. Future Perspectives
  109. References
  110. Genomics of Adipose Tissue
  111. Abstract
  112. White Adipose Tissue and Metabolic Health
  113. Molecular Regulators of Adipocyte Function: Lessons from Monogenic Lipodystrophy
  114. Nuclear Regulators of Adipogenesis
  115. Molecular Regulators of Lipid Synthesis
  116. Molecular Regulators of Lipid Droplet Formation
  117. Molecular Regulators of Lipid Droplet Mobilisation
  118. Molecular Heterogeneity of Regional Adipose Tissue Depots
  119. The Future of Adipose Tissue ‘Genomics’
  120. References
  121. Insights into Molecular Mechanisms and Pathophysiology from Genetics
  122. Translating Genetic Association Signals for Diabetes and Metabolic Traits into Molecular Mechanisms for Disease
  123. Abstract
  124. Functional Characterization of Nonsynonymous Variants
  125. Approaches for Determining Gene Function
  126. Combining Genetic, Epigenetic and Transcript Data
  127. Integrative Approaches, Systems Genetics and Pathway Analysis
  128. Conclusion and Future Perspectives
  129. Acknowledgements
  130. References
  131. Understanding Molecular Mechanisms for Diabetes and Obesity through Mouse Models
  132. Abstract
  133. The Mouse as a Model Organism
  134. The Mouse as a Model for Human Diabetes and Obesity
  135. Genome-Wide Association Study Identifies FTO as an Obesity-Associated Gene
  136. FTO Function
  137. Mouse Models of FTO
  138. Comparison with Human FTO Phenotypes
  139. Where Do We Stand Now?
  140. Conclusions
  141. References
  142. Note Added in Proof by the Editors
  143. References
  144. Clinical Translation
  145. Genetics of Drug Response in Diabetes
  146. Abstract
  147. The Challenges of Defining Drug Response in Diabetes
  148. Variance and Heritability in Distribution and Response to Diabetes Drugs
  149. Key Areas in Diabetes Pharmacogenetics
  150. Monogenic Diabetes
  151. The Role of Transporters – Metformin and Organic Cation Transporters
  152. The Role of Drug Metabolism – Sulphonylureas and CYP450
  153. Type 2 Diabetes Genes and Response
  154. Genome-Wide Association Studies and Metformin – Identifying New Mechanisms
  155. Future Perspectives
  156. Acknowledgements
  157. References
  158. Translating Advances in Our Understanding of the Genetics of Diabetes into the Clinic
  159. Abstract
  160. The Clinical Impact of Genetics on Diagnosing and Treating Rare Forms of Diabetes
  161. The Impact of Genome-Wide Association Studies on Diagnosing Monogenic Diabetes
  162. The Impact of New Sequencing Technologies
  163. The Clinical Impact of an Increased Understanding of the Genetic Basis of Type 2 Diabetes
  164. Understanding of Pathophysiology
  165. Patient Stratification
  166. Predicting Diabetes Risk
  167. Predicting Diabetes Complications and Prognosis
  168. Therapeutic Stratification
  169. Novel Therapeutic Targets

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Tags: Gloyn, Mccarthy, Porta, Matschinsky, Diabetes