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UK BioBank study links gene variants to health

1 November 2021
Appeared in BioNews 1119

Analysis of DNA sequences from over 450,000 participants in the UK BioBank has helped connect hundreds of genes to health outcomes.

Researchers in New York tested the association of around 2.8 million genetic variants in the protein-coding parts of the genome to 3994 different health-related traits – an enormous scale in terms of the quantity of data gathered. They identified 564 genes linked to health, representing a major step forward in the ability to understand the function and impact of genetic variants.

'We illustrate the ability of exome sequencing to identify novel gene-trait associations, elucidate gene function, and pinpoint effector genes underlying genome-wide association study signals at scale' the researchers wrote in their paper.

The study, published in Nature, involved whole-exome sequencing (WES) of each participant to identify coding variants. The 12.3 million variants identified represent a 30 percent increase on the number of coding variants found in all previous WES analyses combined. Variants affecting protein function, including around 1 million loss-off-function variants and around 1.8 million deleterious missense variants, were tested for association with 3994 health-related traits. These included diseases, measurements and proportions of the body, and levels of molecular markers of health and disease.

The team at the Regeneron Genetics Centre discovered 8865 statistically significant associations, involving 564 genes and 492 traits. Numerous risk-increasing variants were found related to liver disease, eye disease and cancer, among others, as well as protective variants linked to lower disease risk. The identification of protective variants is of particular interest as it could inform possible therapeutic strategies, by motivating the design of compounds able to reproduce similar effects in non-carriers. The gene-phenotype associations found in this study can help to better understand numerous gene functions and associated disease pathologies.

The researchers report that to further their studies more detailed health measurements could capture missing variant effects, and whole-genome sequencing could capture non-coding variants missed by WES. Dr Joshua Backman, first author of the paper, has stated that whole-genome sequencing of UK Biobank participants has already commenced.

Finally, the researchers note that there is limited genetic diversity among UK BioBank participants, with the proportion of people with non-European ancestry relatively small. Hence, the involvement of diverse populations in further studies will give insights that are relevant to the genetic disease burden specific to non-Europeans.

The researchers wrote in their paper: 'Accomplishing our original goal of understanding the health consequences of genetic variation in each human gene will likely require sequencing millions of well-characterised and diverse individuals... it is our hope that these results and dataset will help provide the impetus and urgency for generating these new datasets which combine health and variation data on millions of individuals.'

A massive effort links protein-coding gene variants to health
Nature |  25 October 2021
Exome sequencing and analysis of 454,787 UK Biobank participants
Nature |  18 October 2021
Exome sequencing of UK Biobank participants highlights natural variation, gene function
Genomeweb |  19 October 2021
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