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Benefits and limitations of genome-wide association studies

Abstract

Genome-wide association studies (GWAS) involve testing genetic variants across the genomes of many individuals to identify genotype–phenotype associations. GWAS have revolutionized the field of complex disease genetics over the past decade, providing numerous compelling associations for human complex traits and diseases. Despite clear successes in identifying novel disease susceptibility genes and biological pathways and in translating these findings into clinical care, GWAS have not been without controversy. Prominent criticisms include concerns that GWAS will eventually implicate the entire genome in disease predisposition and that most association signals reflect variants and genes with no direct biological relevance to disease. In this Review, we comprehensively assess the benefits and limitations of GWAS in human populations and discuss the relevance of performing more GWAS.

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Fig. 1: GWAS study design.
Fig. 2: Number of loci identified as a function of GWAS sample size.
Fig. 3: GWAS performed to date represent the tip of the iceberg.
Fig. 4: Benefits and limitations of GWAS using SNP arrays.

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Acknowledgements

D.M. holds a Canada Research Chair in Genetics of Obesity. Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. G.P. holds the Canada Research Chair in Genetic and Molecular Epidemiology.

Reviewer information

Nature Reviews Genetics thanks S. Chanock, J. Florez and M. Nelson for their contribution to the peer review of this work.

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V.T., M.T. and D.M. researched the literature. V.T., M.T., Y.B., G.P. and D.M. provided substantial contributions to discussion of the content. V.T., N.P., Y.B. and D.M. wrote the article. M.T., Y.B., G.P. and D.M. reviewed and/or edited the manuscript before submission.

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Correspondence to David Meyre.

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Glossary

Single-nucleotide variants

(SNVs). Single nucleotides in the genome that vary between individuals in a population. Single-nucleotide polymorphism refers to a SNV that occurs at an appreciable frequency in a population (for example, >1%).

Heritability

The proportion of phenotypic variation between individuals in a population that is due to genetic factors.

Rare variants

Variations in the genome for which the less prevalent form (minor allele) occurs at a frequency of 1% or less in the population.

Imputation

Statistical inference of unobserved genotypes from a reference panel of known haplotypes in a population.

Effect sizes

The magnitudes of the effect of alleles on phenotypic values.

Linkage disequilibrium

The nonrandom association of alleles at two or more loci due to limited recombination.

Haplotype

A set of genetic markers that are present on a single chromosome and in linkage disequilibrium.

Common variants

Variation in the genome for which the less prevalent form (minor allele) occurs at a frequency of 5% or greater in the population.

Minor allele frequencies

(MAFs). The frequencies of the less common allele of a genetic variant in a population.

Copy number variants

(CNVs). A class of DNA sequence variants (including deletions and duplications) that lead to a departure from the expected diploid representation of DNA sequence.

Clonal mosaicism

The presence of clones of cells with different karyotypes within an individual derived from a single zygote.

Fine-mapping

The process of localizing association signals to causal variants using statistical, bioinformatic or functional methods.

Epistasis

Statistical interaction between loci in their effect on a trait such that the effect of a genotype at one locus is dependent on the genotypes at the other locus (or loci).

Population stratification

Differences in allele frequencies between cases and controls resulting from systematic differences in ancestry rather than association of genes with disease.

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Tam, V., Patel, N., Turcotte, M. et al. Benefits and limitations of genome-wide association studies. Nat Rev Genet 20, 467–484 (2019). https://doi.org/10.1038/s41576-019-0127-1

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