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Genome-wide association testing beyond SNPs

Nature Reviews Genetics volume 26, pages 156–170 (2025)Cite this article

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Abstract

Decades of genetic association testing in human cohorts have provided important insights into the genetic architecture and biological underpinnings of complex traits and diseases. However, for certain traits, genome-wide association studies (GWAS) for common SNPs are approaching signal saturation, which underscores the need to explore other types of genetic variation to understand the genetic basis of traits and diseases. Copy number variation (CNV) is an important source of heritability that is well known to functionally affect human traits. Recent technological and computational advances enable the large-scale, genome-wide evaluation of CNVs, with implications for downstream applications such as polygenic risk scoring and drug target identification. Here, we review the current state of CNV-GWAS, discuss current limitations in resource infrastructure that need to be overcome to enable the wider uptake of CNV-GWAS results, highlight emerging opportunities and suggest guidelines and standards for future GWAS for genetic variation beyond SNPs at scale.

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Fig. 1: The cumulative total of association studies added to the GWAS Catalog between 2021 and 2023 for SNP- and CNV-based tests.
Fig. 2: Biological and clinical impact of CNV.
Fig. 3: Data flow depicting the key steps from cohort genetic data to CNV-GWAS results.
Fig. 4: Differences between array-based and sequence-based genome resolution for CNV association testing.
Fig. 5: Emerging opportunities.

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Acknowledgements

The authors thank all members of the CNV-GWAS Consortium for contributions and discussions and the EMBL-EBI for funding of the authors’ work.

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Author notes

  1. These authors contributed equally: Laura Harris, Ellen M. McDonagh, Xiaolei Zhang.

Authors and Affiliations

  1. European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI), Wellcome Genome Campus, Hinxton, UK

    Laura Harris, Ellen M. McDonagh, Xiaolei Zhang, Katherine Fawcett, Amy Foreman, Panagiotis I. Sergouniotis, Helen Parkinson, Ewan Birney & Tomas Fitzgerald

  2. Department of Population Health Sciences, University of Leicester, Leicester, UK

    Katherine Fawcett

  3. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK

    Petr Daneck

  4. Division of Evolution, Infection and Genomics, School of Biological Sciences, University of Manchester, Manchester, UK

    Panagiotis I. Sergouniotis

  5. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    Francesco Mazzarotto

  6. National Heart and Lung Institute, Imperial College London, London, UK

    Francesco Mazzarotto

  7. British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Michael Inouye

  8. Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Michael Inouye

  9. Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Australia

    Michael Inouye

  10. Department of Genetics and Genome Biology, University of Leicester, Leicester, UK

    Edward J. Hollox

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Contributions

L.H., E.M.M., X.Z., K.F., P.I.S., F.M., M.I. and T.F. wrote the article. All authors researched the literature, provided substantial contributions to discussions of the content, and reviewed and/or edited the manuscript.

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Correspondence to Tomas Fitzgerald.

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Related links

All of Us: https://allofus.nih.gov/

ClinGen: https://clinicalgenome.org/

Finngen: https://www.finngen.fi/en

Genomics England: https://www.genomicsengland.co.uk/

gnomAD: https://gnomad.broadinstitute.org/

GWAS Catalog: https://www.ebi.ac.uk/gwas/

Linkage disequilibrium: https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/gene-linkage-disequilibrium

Open Targets Platform: https://platform.opentargets.org/

PGS Catalog: https://www.pgscatalog.org/

PharmGKB: https://www.pharmgkb.org/gene/PA128/labelAnnotation

PRECISE: https://npm.sg/

UK Biobank: https://www.ukbiobank.ac.uk/

Supplementary information

Glossary

Cryptic relatedness

Confounding relatedness within a population, which can occur when individuals in the study cohort are more closely related to one another than assumed by the investigators.

Diplotype

The combination of two alleles for a gene, one inherited from each of the individual’s parents.

Dosage sensitivity

When a variation in the number of copies of a gene or genetic element leads to a change in phenotype.

Epistasis

A phenomenon whereby nonlinear interactions between different genes or variants affect the same trait.

FAIR recommendations

A set of guidelines to increase the value of data by making it findable, accessible, interoperable and reusable.

Imputation

A method for inferring genotypes (or genetic variants) at locations that were not included in the assay.

Lead associations

A lead association is the genetic variant that has the strongest association signals (lowest P value) from the association test. This variant may or may not be causal.

LOEUF score

A continuous metric designed to assess how intolerant a gene is to loss-of-function variation.

Mendelian randomization

An epidemiological method used to study the causal effect of a risk factor (such as genetic variation) on health, social or economic outcomes.

Optical mapping

An imaging method that analyses fluorescently labelled DNA molecules to provide a high-resolution map of structural variation.

Polygenic score

(PGS). A weighted estimate of how genetic variants affect a phenotype, often used to estimate a person’s risk of developing a disease or complex trait.

Single-nucleotide polymorphism

(SNP). A germline genetic variant that is present in more than 1% of the population, in which a single nucleotide base differs from the reference genome.

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Harris, L., McDonagh, E.M., Zhang, X. et al. Genome-wide association testing beyond SNPs. Nat Rev Genet 26, 156–170 (2025). https://doi.org/10.1038/s41576-024-00778-y

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