Our latest publication in Nature presents results analysing over 18,000 phenotypes in combination with whole exome sequencing data from nearly 300,000 UK Biobank research participants. The findings, which are being made available to the global scientific community, are uncovering previously unknown insights into the biology of some common diseases that can help accelerate the identification of new therapeutic targets validated by human genetics.
Today, the largest and most comprehensive exome-wide genotype-phenotype dataset currently available has been published in Nature. Conducted by our Centre for Genomics Research (CGR), the analysis highlights novel and important contributions of rare genetic variants to some of the most common diseases.
Advances in human genetic research such as this latest publication are pivotal in helping accelerate the pace of new discoveries in diseases with unmet medical needs. These findings are already yielding promising therapeutic targets that we can take forward into experimental target validation and modelling with the confidence of human-generated insights.
Delving deeper into the data
This study examined exome sequences of 269,171 UK Biobank participants alongside records of 18,780 phenotypes and identified 46,837 variant-level and 1,703 gene-level statistically significant relationships. Additionally, a pan-ancestry analysis explored signals arising from the inclusion of an additional 11,933 UK Biobank participants of African, East Asian and South Asian genetic ancestries.
These gene-phenotype associations, both known ones and new ones linked to human disease, suggest there are substantial contributions from rare genetic variants to some of the most common human diseases. This could help uncover novel disease biology with stronger links to clinically meaningful outcomes and identify new therapeutic targets validated by human genetics.
Accelerating the identification of human-validated gene targets in this way will only improve our ability to test clear biological hypotheses and grow our confidence in the clinical success of the next generation of medicines. This is part of our wider ambition to harness the full power of genomics by analysing up to 2 million genomes by 2026.
Whole-exome sequencing (WES) data for UK Biobank participants were generated as part of the UK Biobank Exome Sequencing Consortium (UKB-ESC) pre-competitive data generation collaboration2. The findings from AstraZeneca’s phenome-wide study have been made available to the global scientific community via AstraZeneca PheWAS portal.
Linking genetics to drug discovery
Research has shown that drug candidates targeting genes clearly linked to human disease are much more likely to demonstrate clinically meaningful efficacy outcomes and therefore, more likely to be approved for patients. This study, based on the in-depth analysis of rare variants in common diseases, suggests that clinically relevant gene-phenotype relationships were enriched seven-fold for targets of FDA-approved medicines. This is higher than previous estimates for target validation traditionally looking at either rare variants in rare diseases (Mendelian genetics) or common variants in common diseases (genome-wide association studies), underscoring the importance of human genetics in target identification and drug discovery.
This study reflects the rapidly evolving pace and scale of human genetics research, and the role that public-private partnerships can play in bringing together diverse skills, adoption of innovative technologies and the generation and analysis of very large datasets to stimulate the development of novel therapies.
A global health resource with unparalleled research opportunities
This research was conducted as part of the UK Biobank Exome Sequencing Consortium (UKB-ESC). The UK Biobank sits at the heart of the UK Life Sciences sector and offers a global health resource with unparalleled research opportunities aimed at improving human health. Today, large private-public consortia such as the UKB-ESC are advancing human genetics research and drug discovery by generating unique, accessible datasets and resources that can be used by the global research community.
This research is another great example where the UK continues to be at the forefront of biomedical research and life sciences, offering unprecedented opportunities for industry and academia to collaborate, innovate and accelerate the way we address some of the biggest challenges in healthcare and medicine.
1. Wang, Q., Dhindsa, R.S., Carss, K. et al. Rare variant contribution to human disease in 281,104 UK Biobank exomes. Nature (2021). https://doi.org/10.1038/s41586-021-03855-y
2. Szustakowski, J.D., Balasubramanian, S., Kvikstad, E. et al. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nat Genet 53, 942–948 (2021). https://doi.org/10.1038/s41588-021-00885-0