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New approaches to population stratification in genome-wide association studies

Abstract

Genome-wide association (GWA) studies are an effective approach for identifying genetic variants associated with disease risk. GWA studies can be confounded by population stratification — systematic ancestry differences between cases and controls — which has previously been addressed by methods that infer genetic ancestry. Those methods perform well in data sets in which population structure is the only kind of structure present but are inadequate in data sets that also contain family structure or cryptic relatedness. Here, we review recent progress on methods that correct for stratification while accounting for these additional complexities.

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Figure 1: P–P plots for the visualization of stratification or other confounders.

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Author information

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Correspondence to Alkes L. Price.

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The authors declare no competing financial interests.

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FURTHER INFORMATION

1000 genomes Project

ADMIXTURE software

EIGENSTRAT, implemented in the EIGENSOFT software

EMMAX software

FBAT software

Nature Reviews Genetics article series on Genome-wide association studies

NHGRI Catalog of Published Genome-Wide Association Studies

PLINK software

QTDT software

ROADTRIPS software

STRUCTURE and STRAT software

TASSEL software

Glossary

Ancestry-informative markers

Genetic markers ascertained for large differences in allele frequency between subpopulations that are genotyped to infer genetic ancestry in new samples.

Armitage trend test

A standard χ2(1 degree of freedom) association test computed as the number of samples times the squared correlation between genotype and phenotype.

Cryptic relatedness

Sample structure due to distant relatedness among samples with no known family relationships.

Differential bias

Spurious differences in allele frequencies between cases and controls due to differences in sample collection, sample preparation and/or genotyping assay procedures.

Exome resequencing

A study design in which exon capture technologies are used to obtain resequencing data covering all exonic regions for each individual in the study.

Family-based association tests

A class of association tests that uses families with one or more affected children as the subjects rather than unrelated cases or controls. The analysis treats the allele that is transmitted to (one or more) affected children from each parent as a 'case' and the untransmitted alleles as 'controls' to avoid the effects of population structure.

Family structure

Sample structure due to familial relatedness among samples.

F ST

A measure of the genetic distance between two populations that describes the proportion of overall genetic variation that is due to differences between populations.

Genetic drift

Random fluctuations in allele frequencies over time due to sampling effects, particularly in small populations.

Genetic heritability

The proportion of the total phenotypic variation in a given characteristic that can be attributed to additive genetic effects. In the broad sense, heritability involves all additive and non-additive genetic variance, whereas in the narrow sense, it involves only additive genetic variance.

Genetic matching

A method of association testing in which cases and controls are matched for genetic ancestry, as inferred by principal components analysis or other methods.

Genomic control

A method for detecting (or detecting and correcting for) stratification based on the genome-wide inflation of association statistics.

Mixed models

A class of models in which phenotypes are modelled using both fixed effects (candidate SNPs and fixed covariates) and random effects (the phenotypic covariance matrix).

Multidimensional scaling

A dimensionality reduction technique, similar to principal components analysis, in which points in a high-dimensional space are projected into a lower-dimensional space while approximately preserving the distance between points.

Population structure

Sample structure due to differences in genetic ancestry among samples.

Principal components analysis

A dimensionality reduction technique used to infer continuous axes of variation in genetic data, often representing genetic ancestry.

Rank statistic

A statistic describing the rank, across markers, of association of each marker. Rank statistics can be transformed into quantiles of a standard normal distribution that can be combined with other statistics.

SNP loadings

The correlations of each SNP to a given principal component in principal components analysis. The principal component coordinates of each sample are proportional to the sum of normalized genotypes weighted by SNP loadings.

Structured association

A method for correcting for stratification in which samples are assigned to subpopulation clusters and evidence of association is stratified by cluster.

Transmission disequilibrium test

A family-based association test involving case–parent trios in which alleles transmitted from parents to children are compared with untransmitted alleles.

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Price, A., Zaitlen, N., Reich, D. et al. New approaches to population stratification in genome-wide association studies. Nat Rev Genet 11, 459–463 (2010). https://doi.org/10.1038/nrg2813

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