Chapter I. Pathogenesis

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

Alan G. Baxter, Margaret A. Jordan

Manuscript submitted December 16, 2012; resubmitted February 2, 2013; accepted February 8, 2013.

Keywords: type 1 diabetes, genome-wide association study, GWAS, HLA, Lyp, IDDM, linkage analysis, polymorphism, haplotype

Abstract

By the year 2000, a draft of the human genome sequence was completed. Millions of single-nucleotide polymorphisms (SNPs) had been deposited into public databases, and high throughput technologies were under development for SNP genotyping. At that time, it was predicted that large case control association studies would provide far better resolution and power than genome-wide linkage studies. Type 1 diabetes was one of the first phenotypes to be examined by genome-wide association studies (GWAS), and to date over 50 genomic regions have been associated with the disease. In general, the great majority of these loci individually contribute a relatively small degree of risk, and most loci lie outside of coding sequences. The identification of molecular mechanisms from these genomic data therefore remains a significant challenge. Here, we summarize genetic candidate, linkage, and association studies of type 1 diabetes and discuss a potential strategy to identify mechanisms of disease from genomic data.

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