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  • Published:

Genetic insights into common pathways and complex relationships among immune-mediated diseases

Nature Reviews Genetics volume 14, pages 661–673 (2013)Cite this article

Subjects

Key Points

  • The Immunochip platform has facilitated comparison of the molecular genetic architecture of many immune-mediated diseases.

  • Many genetic susceptibility loci are shared between immune-mediated diseases, but the 'sharing' is complex and includes considerable discordancy (that is, alleles that have opposite effects on the risks of different diseases) and allelic heterogeneity (that is, different polymorphisms in the same region are associated with different diseases).

  • Concordant sharing tends to cluster immune-mediated diseases according to seropositive or seronegative status, but there are some notable exceptions that may partly underpin the clinically distinct phenotypes.

  • Large effect size susceptibility loci tend to be phenotype-specific.

  • Immunochip studies have shown that fine mapping using dense SNP genotyping in large cohorts substantially refines many association intervals, enabling the credible set to be reduced to one or a handful of candidate causal variants for a sizable proportion of susceptibility loci.

  • Major challenges remain in defining causal variants for all association intervals, understanding their functional impact and defining in which cells they exert their effects.

  • The extent to which low-frequency and rare variants contribute to immune-mediated disease susceptibility, and whether these may also be shared between diseases, is currently unknown.

Abstract

Shared aetiopathogenic factors among immune-mediated diseases have long been suggested by their co-familiality and co-occurrence, and molecular support has been provided by analysis of human leukocyte antigen (HLA) haplotypes and genome-wide association studies. The interrelationships can now be better appreciated following the genotyping of large immune disease sample sets on a shared SNP array: the 'Immunochip'. Here, we systematically analyse loci shared among major immune-mediated diseases. This reveals that several diseases share multiple susceptibility loci, but there are many nuances. The most associated variant at a given locus frequently differs and, even when shared, the same allele often has opposite associations. Interestingly, risk alleles conferring the largest effect sizes are usually disease-specific. These factors help to explain why early evidence of extensive 'sharing' is not always reflected in epidemiological overlap.

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Figure 1: Relationship between sample size and the number of associated loci with genome-wide significance.
Figure 2: Associations of components of the IL-23R response pathway with immune-mediated diseases.
Figure 3: Associations of components of the major histocompatibility complex class I antigen processing pathway with immune-mediated diseases.

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Acknowledgements

M.P. is supported by the UK National Institute for Health Research (NIHR) Biomedical Research Centre award to Addenbrooke's Hospital and University of Cambridge School of Clinical Medicine. D.A.v.H. is funded by the UK Medical Research Council (G1001158). M.A.B. is supported by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship.

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Author notes

  1. Miles Parkes and Adrian Cortes: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK

    Miles Parkes

  2. The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Road, Woolloongabba, Brisbane, QLD 4102, Australia

    Adrian Cortes & Matthew A. Brown

  3. Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, E1 2AT, UK

    David A. van Heel

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Correspondence to Miles Parkes.

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PowerPoint slides

Supplementary information

Supplementary information S1 (figure)

Circos plots illustrate sharing between loci associated with six immune mediated diseases (IMDs): ankylosing spondylitis (AS), celiac disease (CeD), inflammatory bowel disease (IBD; Crohn's disease plus ulcerative colitis), psoriasis (Ps), rheumatoid arthritis (RA), and type 1 diabetes (T1D). (PDF 5224 kb)

Supplementary information S2 (box)

Correlation of SNPs within pleiotropic loci (PDF 193 kb)

Supplementary information S3 (table)

Supplementary tables 1–6 (XLS 148 kb)

Glossary

Deep replication

Attempted replication of a long list of single-nucleotide polymorphisms (SNPs) for which there is some evidence of association in index genome-wide association studies (GWASs) or GWAS meta-analyses. Most studies attempt to replicate a modest number of SNPs (5 to 100); Immunochip studies attempted this for the top 2,000 independent association signals for each phenotype.

Seropositive

The presence of antibodies that are directed against one or more of an individual's own proteins (known as autoantibodies). For example, there are anti-tissue transglutaminase antibodies in coeliac disease, and anticitrullinated peptide antibodies in rheumatoid arthritis.

Seronegative

The absence of antibodies that are directed against one or more of an individual's own proteins (known as autoantibodies).

Auto-inflammatory

A disease, usually of mostly unknown aetiology, in which the immune response seems to be directed against 'self' antigens. The term may be used to include antibody- mediated disease as well as non-autoantibody-mediated pathology.

Pleiotropic

The phenomenon in which variants in a single gene are responsible for several distinct and seemingly unrelated phenotypic effects.

Linkage disequilibrium

(LD). The non-random association of two or more alleles. Alleles that are in LD are found together on the same haplotype more often than would be expected under a random combination of alleles. The pattern of LD in a given genomic region reflects the history of natural selection, mutation, recombination, genetic drift and other demographic and evolutionary forces.

Minor allele frequency

In a population, the frequency of the less common allele of a genetic variant. It has a value of between 0 and 0.5, and may vary among populations.

HLA class II

(Human leukocyte antigen class II). Part of the human chromosome 6 major histocompatibility complex region that encodes HLA-DP, -DQ and -DR alleles. These are expressed on professional antigen-presenting cells and present antigens from extracellular proteins such as those derived from pathogens to CD4+ T cells.

HLA class I

(Human leukocyte antigen class I). Part of the human chromosome 6 major histocompatibility complex region that encodes HLA-A, -B and -C. These molecules can present antigen from inside the cell (including virally encoded proteins) to other immune cells, and are present on most cell types.

Shared epitope

The hypothesis that a subregion of the human leukocyte antigen DR (HLA-DR) molecule involved in peptide presentation is important in rheumatoid arthritis pathogenesis.

TH17 lymphocytes

(T helper 17 lymphocytes). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases.

TH1 lymphocytes

(T helper 1 lymphocytes). A subset of T helper cells that produce interferon-γ (and other cytokines) and that activate macrophages.

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Parkes, M., Cortes, A., van Heel, D. et al. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 14, 661–673 (2013). https://doi.org/10.1038/nrg3502

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