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  • Review Article
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Genome-wide association studies: a new window into immune-mediated diseases

Nature Reviews Immunology volume 8, pages 631–643 (2008)Cite this article

Key Points

  • Genome-wide association (GWA) studies have dramatically influenced our ability to identify genetic risk factors for complex immune-mediated diseases.

  • We provide the information necessary for immunologists to better understand the rapid advances in our knowledge of genetic variation and in the technologies to probe this variation, which have enabled GWA studies. In addition, both the analytical challenges and the strengths of these types of studies are discussed.

  • GWA studies of immune-mediated diseases, including Crohn's disease, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus, have enabled the discovery of previously unknown factors that influence disease susceptibility and/or pathology.

  • Knowledge gained from these GWA studies can reveal how previously unrecognized biological pathways might contribute to disease pathogenesis. This research points toward the involvement of some pathways that are specific to one immune-mediated disease and others that are common to several different diseases.

  • Despite the success of GWA studies, several challenges lie ahead: how can we complete the mechanistic picture of how genetic variation in multiple different genes leads to disease development? How will these data impact the design of future immunology studies, and how can we apply this knowledge to clinical practice in the future?

Abstract

Given the recent explosion of genetic discoveries, 2007 is becoming known to human geneticists as the year of genome-wide association studies. In fact, more genetic risk factors for common diseases were identified in this one year than had been collectively reported before 2007. In particular, 2007 witnessed the discovery of many genes that influence susceptibility to individual immune-mediated diseases, as well as other genes that are associated with susceptibility to more than one disease. Although much work remains to be done, in this Review we discuss what effect these studies are having on our understanding of disease pathogenesis and their potential impact on future immunology studies.

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Figure 1: Schematic representation of cell-specific signalling pathways mediated by Crohn's disease susceptibility genes.
Figure 2: Interactions between innate immune cells and adaptive immune cells are central to rheumatoid arthritis and SLE pathogenesis.
Figure 3: Work flow placing candidate genes in disease-specific signalling pathways.

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Acknowledgements

The authors would like to thank C. Lefebvre, A. Huett, A. Ng and C. Labbé for their help in the preparation of this manuscript. R.J.X. is supported by grants from the National Institutes of Allergy and Immunology (AI062773), National Institutes of Diabetes, Digestive and Kidney Disease (DK43,351) and CCIB development funds. J.D.R. is funded by grants from the National Institutes of Allergy and Infectious Diseases (AI065687; AI067152), from the National Institute of Diabetes and Digestive and Kidney Diseases (DK064869; DK062432) and from the Crohn's and Colitis Foundation of America (SRA512).

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Authors and Affiliations

  1. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Ramnik J. Xavier

  2. Université de Montréal and the Montreal Heart Institute, Research Center, 5000 Bélanger Street, Montreal, H1T 1C8, Quebec, Canada

    John D. Rioux

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Correspondence to John D. Rioux.

Related links

Glossary

Causal gene

The specific gene that is responsible for disease risk conferred by a genomic region that has been identified by an association.

Linkage studies

Studies aimed at establishing linkage between a genetic marker and a disease locus. Linkage is based on the tendency of genes and genetic markers to be inherited together because of their proximity on the same chromosome.

Tag SNPs

Representative SNPs in a region of the genome with high linkage disequilibrium. Tag SNPs allow a reduction in the number of SNPs that must be genotyped while allowing the generation of the same amount of information. The HapMap Project catalogued tag SNPs in the entire genome.

Hardy–Weinberg equilibrium

A fundamental principle in genetics stating that the genotypic frequencies of a large, randomly mating population remain constant in the absence of mutation, migration, natural selection or random drift.

Penetrance

The probability, under given environmental conditions, with which a specific phenotype is expressed by individuals with a specific genotype. For example, if 50% of the people with a gene 'X' that is known to cause a disease do in fact develop the disease, then the penetrance of that gene is 0.5.

Genome-wide linkage scan

A linkage study carried out with markers located across the entire genome. Linkage studies were traditionally carried out with ∼300 markers of simple sequence-length repeats and more recently with ∼5,000 single-nucleotide polymorphisms.

Genetic markers

Genomic variants used as positional tools to find associations between specific DNA fragments and a certain phenotype or disease.

Single-nucleotide polymorphisms

(SNPs). Genomic variants in which a single base in the DNA differs from the usual base at that position. SNPs are the most common type of variation in the human genome.

Linkage disequilibrium

A situation in which alleles in a chromosomal region occur together more often than can be accounted for by chance, indicating that the alleles are in close proximity on the DNA strand and are most likely to be passed on together within a population.

Haplotype

A combination or pattern of alleles at multiple linked loci that are inherited together.

HapMap

A genetic resource created by the International HapMap Project (see the International HapMap website). The HapMap is a catalogue of common genetic variants that occur in humans. It describes what these variants are, where they occur in the genome and how they are distributed among people within populations and among populations in different parts of the world.

Genotyping

A test designed to identify the genetic constitution of an individual — that is, the alleles present at one or more specific loci.

Alleles

Alleles are alternative forms of genes that are located at a specific position on a specific chromosome. In association studies, the term allele is most commonly used to refer to one variant of a marker.

Causal variant

The specific DNA sequence that functionally gives rise to the increased risk conferred by the causal gene or genomic region identified by an association.

Copy-number variant

(CNV). A genomic variant characterized by differences in the number of copies of specific repeated DNA fragments that range from 1 kb to several Mb long. CNVs can contain entire genes and can be used as markers in association studies.

Association testing

A statistical approach that tests for association between marker or candidate gene alleles and diseases. If a correlation is observed between genotype and phenotype, there is said to be an association between the marker or allele and the disease or trait.

Replication studies

Studies designed to test (or replicate) a prior and explicit genetic hypothesis. For example, replication studies are carried out to validate the findings of a genome-wide association study, thereby discriminating false positives from true positives identified in the study.

Autophagy

A cellular process in which cytoplasmic organelles and macromolecular complexes are entrapped in double-membrane-bound vesicles for delivery to lysosomes and subsequent degradation. This process is involved in constitutive turnover of proteins and organelles and is central to cellular activities that maintain a balance between synthesis and breakdown of various proteins.

Gene desert

A large genomic segment devoid of genes. Gene deserts tend to harbour limited sequence conservation. The rare conserved region can contain transcriptional regulatory elements.

Odds ratios

Measures of relative risk, usually estimated from studies that compare patients with control subjects. In a genetic disease context, the odds ratio is defined as the ratio of the odds of having an allele or a genotype while being affected by the disease to the odds of having the same allele or a genotype while being a healthy control.

B-1 cells

B cells that express the cell-surface molecule CD5, which can bind to another B-cell-surface protein, CD72. CD5–CD72 interactions are thought to mediate B-cell–B-cell interactions. B-1 cells are mainly found in the peritoneum and have a role in T-cell-independent antibody production.

Locus

The specific position of a gene or a marker on a chromosome.

TH17 cells

(T helper 17 cells). 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. Their generation involves transforming growth factor-β (TGFβ), IL-6, IL-23 or IL-21, IL-1β and the transcription factors RORγt and STAT3.

Immunoreceptor tyrosine-based activation motifs

(ITAMs). ITAMs are protein motifs that exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases. This motif may be dually phosphorylated on tyrosines that link antigen receptors to downstream signalling molecules.

Knock-in and knockout models

Animal models generated through molecular biology experiments that aim to delete the expression of endogenous genes (knock-out) or to introduce a specific allele of a given gene (knock-in).

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Xavier, R., Rioux, J. Genome-wide association studies: a new window into immune-mediated diseases. Nat Rev Immunol 8, 631–643 (2008). https://doi.org/10.1038/nri2361

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