In the 1960s, the American Geneticist J.V. Neel referred to diabetes as the 'geneticists nightmare' owing to the high probability that the phenotype was heterogeneous, not clearly defined with a variable age of onset and a strong environmental influence. In the 1970s, the distinction between autoimmune (type 1 diabetes) and non-autoim-mune (type 2 diabetes) was made clarifying a major cause of the disease heterogeneity. Through the 1990s, the discovery of the genes involved in mendelian forms of diabetes demonstrated the enormous power of human genetics to uncover fundamental insights into glucose homeostasis and to inform on treatment and prognosis for patients with particular genetic subtypes of diabetes. The genetic basis of type 2 diabetes, however, remained elusive.A\In recent years, the field of human genetics discovery has been revolutionised by publically funded initiatives such as the Human Genome Project, HapMap and 1000 Genomes projects. These, in tandem with technological advances such as array geno-typing and next-generation sequencing, have enabled genome-wide studies of genetic variation in previously unimaginable sample numbers. This has in turn led to an explosion in the number of genetic loci robustly implicated in type 2 diabetes risk.A\In writing this book, we have called upon a number of our colleagues who, over the years, have been part of highly collaborative international efforts to advance our understanding of the genetic basis of type 2 diabetes and related traits. We are indebted to them for agreeing to help us with capturing this journey. They have described the huge progress that has been made, whilst at the same time outlining the substantial challenges that lie ahead if we are to fully capitalise on the these discoveries and translate our improved understanding of the genetic basis of type 2 diabetes into advances in clinical care. Anna L. Gloyn, Oxford; Mark I. McCarthy, Oxford

Preface VII

Gene Discovery Efforts for Type 2 Diabetes

Genome-Wide Association Studies in Type 2 Diabetes 1

Fine Mapping Type 2 Diabetes Susceptibility Loci 14

Whole Genome and Exome Sequencing of Type 2 Diabetes 29

Gene Discovery Efforts for Glycaemic and Metabolic Traits

Genome-Wide Association Studies of Glycaemic Traits: A MAGICal Journey 42

Genome-Wide Association Studies of Obesity and Related Traits 58

Gene Discovery Efforts for Monogenic Disorders of β-Cell Dysfunction and Insulin Resistance

Next-Generation Sequencing for the Diagnosis of Monogenic Diabetes and Discovery of Novel Aetiologies 71

Whole-Exome Sequencing of Patients with Severe Disorders of Insulin Action 87

'Omics'of Type 2 Diabetes and Related Traits

Epigenetic Modifications and Type 2 Diabetes in Humans 102

Insights into β-Cell Biology and Type 2 Diabetes Pathogenesis from Studies of the IsletTranscriptome 111

Genomics of Adipose Tissue 122

Insights into Molecular Mechanisms and Pathophysiology from Genetics

Translating Genetic Association Signals for Diabetes and Metabolic Traits into Molecular Mechanisms for Disease 133

Understanding Molecular Mechanisms for Diabetes and Obesity through Mouse Models 146

Clinical Translation

Genetics of Drug Response in Diabetes 158

Translating Advances in Our Understanding of the Genetics of Diabetes into the Clinic 173

Author Index 187

Subject Index 188

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