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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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.
Nature Reviews Genetics thanks S. Chanock, J. Florez and M. Nelson for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- 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%).
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.
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.
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.
The process of localizing association signals to causal variants using statistical, bioinformatic or functional methods.
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.