How rare mutations contribute to complex traits

Evans, Luke M.; Romero Villela, Pamela N.

doi:10.1038/d41586-023-00272-1

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08 February 2023

How rare mutations contribute to complex traits

An analysis of rare genetic variants reveals that they influence human traits through similar biological pathways to common ones. The work deepens our understanding of how this type of variant affects complex traits.

Luke M. Evans
1. Luke M. Evans is at the Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado 80303, USA, and in the Department of Ecology and Evolutionary Biology, University of Colorado Boulder.
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Pamela N. Romero Villela
1. Pamela N. Romero Villela is at the Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado 80303, USA, and in the Department of Psychology and Neuroscience, University of Colorado Boulder.
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Our understanding of the genetic mutations that affect complex human traits — such as height, smoking-related behaviour or the risk of diabetes — has been vastly broadened by genome-wide association studies (GWASs). But such research has focused largely on associations between traits of interest and variants that are common in the human population. Rare variants pose challenges to GWASs, because they can be studied using only large samples and in-depth genetic information, and can be more strongly confounded by non-genetic factors than can common variants, increasing the chance of spurious findings¹. Until now, therefore, researchers have been unable to assess accurately whether rare variants contribute substantially to complex traits. Writing in Nature, Weiner et al.² introduce a new approach to address this question. They find that, although rare variants account for a much smaller proportion of heritability than do common variants, they act through the same genes and biological pathways.

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Nature 614, 418-419 (2023)

doi: https://doi.org/10.1038/d41586-023-00272-1

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