Research Press Release

Genetics: gnomAD project improves the interpretation of genomes


May 28, 2020

The largest-known public catalogue of genetic variants in humans, presented by the Genome Aggregation Database (gnomAD), provides a resource for improving our understanding of human gene functions and for discovering new disease-associated genes. The application of this dataset, collected from samples from more than 140,000 people, is described in a collection of papers in Nature, Nature Communications and Nature Medicine.

The function of most genes in the human genome is unknown. One way of discovering the function of a gene is to observe what happens when the gene is disrupted by a mutation. These variants often have adverse outcomes and are usually rare. Large genetic sequencing studies provide an opportunity to examine the effects of these loss-of-function variants, which could provide important insights into human biology and diseases.

In an overview paper in Nature, Konrad Karczewski and colleagues present a catalogue of 443,769 predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets. The authors go on to assess whether these variants that are predicted to prevent normal functioning of the resulting protein would have little to no effect on physiology, or would cause serious health issues. Two accompanying papers in Nature use this dataset to create a resource of structural variants and assess the impact of deleting, duplicating, or even inverting the orientation of genes.

Other papers in the collection show how human loss-of-function variants can be used to evaluate candidate drug targets, improve the clinical interpretation of genetic variants, or investigate specific loss-of-function variants in more detail. For example, in Nature Medicine, Nicola Whiffin and colleagues analyse variants in a gene associated with increased risk of Parkinson’s disease, and the results suggest that targeting this gene is a potentially safe treatment option.

The size of the sample collected by the gnomAD project is more than twice that of its predecessor, in which more than 60,000 exomes were compiled by the Exome Aggregation Consortium (ExAC). However, Karczewski and colleagues note that they remain far from identifying all predicted loss-of-function variants in humans. Nevertheless, they suggest that the resource provides an opportunity to improve our assessment of rare and common genetic diseases.


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