Elsevier

Seminars in Immunology

Volume 21, Issue 6, December 2009, Pages 355-362
Seminars in Immunology

Review
Genome-wide association studies in type 1 diabetes, inflammatory bowel disease and other immune-mediated disorders

https://doi.org/10.1016/j.smim.2009.06.001Get rights and content

Abstract

Genome-wide association studies have delivered on the promise of uncovering genetic determinants of complex disease. In this review, we provide a summary of recent advances in the identification of multiple variants associated with autoimmune-mediated disorders; specifically type 1 diabetes and inflammatory bowel disease. Sixteen loci, all replicated in independent samples, have now been uncovered for type 1 diabetes and in excess of 40 for inflammatory bowel disease. The next steps are to identify the true causal variants underlying evidence of disease association and to leverage this information to improve diagnosis, prevention and cure of these diseases.

Section snippets

Approaches to analysis of complex genetic traits

Prior to the availability of platforms for genome-wide association (GWA) analyses, efforts to uncover the genetic underpinnings of a given complex disease were focused on association studies of ‘candidate’ genes, selected based on biological reasoning that the gene product was involved in the pathogenesis of the disease, as well as family-based linkage studies. Some extremely important discoveries of type 1 diabetes variants were made by these approaches, including identification of strong

Type 1 diabetes

Type 1 diabetes (T1D) is a disease that results from autoimmune destruction of pancreatic beta cells, resulting in a lack of production of insulin. T1D represents approximately 10% of all cases of diabetes and is most prevalent in populations of European ancestry, where the is ample evidence of increased annual incidence during the past 5 decades [42], [43].

T1D risk is strongly influenced by multiple genetic loci and as yet poorly understood environmental factors. The disease is highly

Inflammatory bowel disease

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology involving multiple genes and environmental factors. The two IBD subtypes, Crohn's disease (CD) and ulcerative colitis (UC) present most commonly during the second and third decades of life [72]. They are characterized respectively by confluent inflammation of the colonic mucosa (UC) and discontinuous transmural intestinal inflammation (CD). IBD is thought to develop as a result of dysregulation of immune

Other immune-mediated disorders

There are hundreds of immune-mediated diseases known to impact humans. However, some are much more prevalent than others, with asthma, ankylosing spondylitis, systemic lupus erythematosus and rheumatoid arthritis being among the most common. As such, for these given disorders there have been sufficient sample sizes to also investigate them with the GWA approach.

Moffatt et al. [112] reported a GWA of 500,000 SNPs in childhood onset asthma where they genotyped nearly 1000 patients and 1200

Discussion

The advent of genome-wide platforms to capture SNP variation has enhanced our understanding of the genetic basis of complex diseases, such as type 1 diabetes and inflammatory bowel disease. Indeed, over the last 3 years, notable discoveries of variants impacting multiple complex diseases and related traits have been reported, and replicated by independent groups. Type 1 diabetes and inflammatory bowel disease have been success stories in this context, yielding many new genes and, indeed, have

References (129)

  • D.R. Gaya et al.

    New genes in inflammatory bowel disease: lessons for complex diseases?

    Lancet

    (2006)
  • J. Halfvarson et al.

    Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics

    Gastroenterology

    (2003)
  • J. Hampe et al.

    Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations

    Lancet

    (2001)
  • M.M. Mirza et al.

    Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease

    American Journal of Human Genetics

    (2003)
  • R.N. Baldassano et al.

    Association of variants of the interleukin-23 receptor gene with susceptibility to pediatric Crohn's disease

    Clinical Gastroenterology and Hepatology

    (2007)
  • R.H. Duerr et al.

    High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12

    American Journal of Human Genetics

    (2000)
  • J. Hampe et al.

    A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort

    American Journal of Human Genetics

    (1999)
  • K.E. Lohmueller et al.

    Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease

    Nature Genetics

    (2003)
  • J.N. Hirschhorn et al.

    Genome-wide association studies for common diseases and complex traits

    Nature Reviews

    (2005)
  • C.S. Carlson et al.

    Mapping complex disease loci in whole-genome association studies

    Nature

    (2004)
  • The International HapMap Project

    Nature

    (2003)
  • A haplotype map of the human genome

    Nature

    (2005)
  • F.J. Steemers et al.

    Whole-genome genotyping with the single-base extension assay

    Nature Methods

    (2006)
  • K.L. Gunderson et al.

    A genome-wide scalable SNP genotyping assay using microarray technology

    Nature Genetics

    (2005)
  • D. Reich et al.

    A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility

    Nature Genetics

    (2005)
  • L.R. Cardon et al.

    Association study designs for complex diseases

    Nature Reviews

    (2001)
  • R.J. Klein et al.

    Complement factor H polymorphism in age-related macular degeneration

    Science

    (2005)
  • A.O. Edwards et al.

    Complement factor H polymorphism and age-related macular degeneration

    Science

    (2005)
  • J.L. Haines et al.

    Complement factor H variant increases the risk of age-related macular degeneration

    Science

    (2005)
  • G. Thorleifsson et al.

    Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma

    Science

    (2007)
  • R. Sladek et al.

    A genome-wide association study identifies novel risk loci for type 2 diabetes

    Nature

    (2007)
  • Wellcome Trust Case–Control Consortium

    Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls

    Nature

    (2007)
  • R. Saxena et al.

    Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels

    Science

    (2007)
  • E. Zeggini et al.

    Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes

    Science

    (2007)
  • L.J. Scott et al.

    A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants

    Science

    (2007)
  • V. Steinthorsdottir et al.

    A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

    Nature Genetics

    (2007)
  • J.C. Florez et al.

    A 100K genome-wide association scan for diabetes and related traits in the Framingham Heart Study: replication and integration with other genome-wide datasets

    Diabetes

    (2007)
  • R.L. Hanson et al.

    A search for variants associated with young-onset type 2 diabetes in American Indians in a 100K genotyping array

    Diabetes

    (2007)
  • E. Rampersaud et al.

    Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations

    Diabetes

    (2007)
  • M.G. Hayes et al.

    Identification of type 2 diabetes genes in Mexican Americans through genome-wide association studies

    Diabetes

    (2007)
  • A. Helgadottir et al.

    A common variant on chromosome 9p21 affects the risk of myocardial infarction

    Science

    (2007)
  • R. McPherson et al.

    A common allele on chromosome 9 associated with coronary heart disease

    Science

    (2007)
  • D.F. Gudbjartsson et al.

    Variants conferring risk of atrial fibrillation on chromosome 4q25

    Nature

    (2007)
  • S. Kathiresan et al.

    Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans

    Nature Genetics

    (2008)
  • C.J. Willer et al.

    Newly identified loci that influence lipid concentrations and risk of coronary artery disease

    Nature Genetics

    (2008)
  • J.S. Kooner et al.

    Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides

    Nature Genetics

    (2008)
  • J. Gudmundsson et al.

    Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24

    Nature Genetics

    (2007)
  • M. Yeager et al.

    Genome-wide association study of prostate cancer identifies a second risk locus at 8q24

    Nature Genetics

    (2007)
  • C.A. Haiman et al.

    Multiple regions within 8q24 independently affect risk for prostate cancer

    Nature Genetics

    (2007)
  • I. Tomlinson et al.

    A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21

    Nature Genetics

    (2007)
  • Cited by (20)

    • Inflammatory bowel disease

      2011, Primary Care - Clinics in Office Practice
      Citation Excerpt :

      Hence, despite the fact that genetic factors are important, more so in CD than UC, it is evident that environmental factors also play a key role. Genome-wide association studies have revealed more than 40 susceptibility loci for IBD, some associated specifically with either CD or UC and others associated with both.15 Prominent among these findings are the IBD1 gene encoding the protein NOD2 (also called CARD15) in CD, OCTN1/2 within the IBD5 locus in CD and UC, ATG16L in CD, IRGM1 in CD, and IL23R in CD and UC.16

    • Enhancement of deoxyribonucleic acid microarray performance using post-hybridization signal amplification

      2010, Analytica Chimica Acta
      Citation Excerpt :

      DNA microarray technology has revolutionized nucleic acid-based research due to its ability to run a vast number of parallel reactions simultaneously and provide high-throughput data analysis. While traditional uses of microarrays have focused predominantly on gene expression profiling and genotype analysis, the broad utility of the technology has prompted its application to a number of disparate fields including autoimmune disease analysis [1,2], environmental studies [3,4], cancer genomics [5–7], and biodefense [8]. Microarray performance is critically dependent upon its ability to demonstrate sufficient specificity and sensitivity for targets.

    View all citing articles on Scopus
    1

    Center for Applied Genomics, 1216F Abramson Research Center, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318, USA. Tel.: +1 267 426 2795; fax: +1 267 426 0363.

    View full text