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HUMAN GENETICS

The power of large-scale exome sequencing

Nature Reviews Genetics volume 22, page 549 (2021)Cite this article

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Over the past decade, the ability to investigate protein-coding regions using high-throughput sequencing has been a cornerstone of human disease genetics, driving the discovery of genes associated with many diseases. When initially conceived, whole-exome sequencing (WES) focused on identifying mutations that caused rare monogenic disorders. Now, a study in Science shows that application of this technology to very large population samples can have profound, revelatory impact also on common complex diseases, such as obesity. In a second paper, published in Nature Genetics, the UK Biobank Exome Sequencing Consortium (UKB-ESC) reports interim results of their efforts to generate WES data for all ~500,000 participants in the UK Biobank for the purpose of accelerating the use of rare coding variation to inform drug discovery.

In vitro experiments suggested that loss of function for some contributing variants was due to cellular retention of a truncated receptor. In addition, Gpr75 knockout in mice fed a high-fat diet was protective against weight gain and its related disruption of glucose and insulin metabolism. These effects were allele-dose dependent, with heterozygous and homozygous knockout animals showing 25% and 44% less weight gain than wild-type animals. Given that candidate drug targets with supporting evidence of human genetic disease association are twice as likely to lead to approved drugs, Akbari et al. propose GPR75 inhibition as a potential therapeutic strategy to tackle obesity.

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References

Original articles

  • Akbari, P. et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science 373, eabf8683 (2021)

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  • Szustakowski, J. D. et al. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nat. Genet. 53, 942–948 (2021)

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  1. Nature Reviews Genetics http://www.nature.com/nrg/

    Linda Koch

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  1. Linda Koch
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Correspondence to Linda Koch.

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Koch, L. The power of large-scale exome sequencing. Nat Rev Genet 22, 549 (2021). https://doi.org/10.1038/s41576-021-00397-x

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