Review Article | Published:

Rare and common variants: twenty arguments

Nature Reviews Genetics volume 13, pages 135145 (2012) | Download Citation


Genome-wide association studies have greatly improved our understanding of the genetic basis of disease risk. The fact that they tend not to identify more than a fraction of the specific causal loci has led to divergence of opinion over whether most of the variance is hidden as numerous rare variants of large effect or as common variants of very small effect. Here I review 20 arguments for and against each of these models of the genetic basis of complex traits and conclude that both classes of effect can be readily reconciled.

Key points

  • For the past couple of years, discussion of the so-called 'missing heritability problem' has focused attention on the failure of genome-wide association studies (GWASs) to discover more than a minor fraction of the genetic variance for complex traits and disease susceptibility.

  • However, it now appears that the problem is largely a result of the small contribution of most variants, either because the variants are too rare to contribute population-wide, or because the effect sizes of common variants are, in general, very small.

  • This Review presents five arguments for, and five against, each of these two models and concludes that although the infinitesimal model is essentially correct, rare alleles of large effect almost certainly also make an essential contribution to risk of disease. Some of the more important arguments are listed below.

  • Standard evolutionary and quantitative genetic theory both provide strong expectations for rare and common variant contributions. There is also increasingly solid empirical evidence for both classes of contribution.

  • Neither model can yet be said to provide compelling explanations for epidemiological transitions and other demographic phenomena, including familial clustering and sibling resemblance.

  • Mechanistic explanations for additive within-locus effects and multiplicative between-locus effects are ultimately desired to complement a purely statistical description of effects. In either model, the majority of healthy individuals carry disease-associated alleles.

  • Although common variants may establish the background liability to many complex diseases, environmental and rare variant perturbations often provide the extra impetus that pushes an individual over the disease threshold.

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I particularly thank F. Vannberg, D. Goldstein, P. Visscher and E. Cirulli for discussions and suggestions and the Georgia Institute of Technology and the US National Institutes of Health for funding.

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  1. School of Biology and Center for Integrative Genomics, 770 State Street, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.

    • Greg Gibson


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The author declares no competing financial interests.

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Correspondence to Greg Gibson.


Common disease–common variant hypothesis

(CDCV hypothesis). The model that complex disease is largely attributable to a moderate number of common variants, each of which explains several per cent of the risk in a population.


The proportion of the phenotypic variance in a population that is due to genotypic differences among individuals.

Genetic variance

The contribution of genotypic differences among individuals to phenotypic variation.

Narrow sense variance

The additive component of the genetic variance: namely, the average effect of substituting one allele for another at a locus.

Genotype relative risk

(GRR). The ratios of the risk of disease between individuals with and without the genotype. A ratio of 1.1 equates to a 10% increase in risk.


Describes the proportion of individuals with a mutation or risk variant who have the disease.


The severity of the disease in individuals who have the risk variant and disease.

Genotype-by-genotype interactions

(G×G interactions). Otherwise known as epistasis, this refers to the situation in which the effect of one genotype is conditional on genotypes at one or more other unlinked loci.

Genotype-by-environment interactions

(G×E interactions). Refers to the situation in which the effect of the genotype is conditional on the environment, which may include abiotic (temperature), biotic (viral exposure) and cultural/behavioural influences.

Parent-of-origin genetic contributions

Genetic effects that are only seen when the allele is transmitted either from the mother or from the father.

Purifying selection

Selection against genetic variants that reduce fitness. Purifying selection generally keeps deleterious alleles at a low frequency or removes them from the population.

Chronic disease

Medical conditions that develop slowly and persist, generally with a strong genetic component.


A class of diseases due to disruption of the cilium, a cellular organelle.

Linkage disequilibrium

(LD). Nonrandom association between genotypes, generally discussed in relation to loci that are closely located on a chromosome: for example, within a gene.


A set of alleles that commonly segregate together and are defined as regions of extended linkage disequilibrium, which in humans is often up to 100 kb in length.

Mutation–selection balance

An evolutionary model that accounts for the maintenance of genetic variation as a balance between mutation generating variance and purifying selection removing it.


The notion that genetic systems evolved to be buffered but that large effect mutations or environmental change can overcome this buffering, thereby increasing the genetic variance.

Genomic selection

The use of genetic markers that are spread throughout the genome to select individuals with desired predicted breeding values.

Predicted breeding value

The estimated phenotype of progeny of individuals that have a particular genotype.

Threshold-dependent models

A model that postulates that individuals who exceed some threshold value of a continuous physiological characteristic (called 'liability') have or are at high risk for disease.


Intermediate physiological or psychological traits, such as metabolite and transcript abundance or a specific neuronal function.

Expression quantitative trait locus analysis

(eQTL analysis). Studies of the association between genotypes and gene expression (transcript abundance), leading to the detection of eQTLs.

Cryptic variation

Genetic variation with effects that are only seen under perturbed conditions, such as in the presence a particular mutation or environmental exposure.

Transgressive segregation

The appearance of traits in the offspring that are more extreme than those observed in either parent.

Beavis effect

Also called the 'winner's curse', this is the observation that the effect sizes estimated in a discovery sample tend to be overestimates of the true effect sizes, as they typically receive the benefit of sampling variance in the same direction as the true effect in order to exceed strict genome-wide significance levels.

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